TW200403216A - A sulfonated amine acid derivative and the metalloproteinase inhibitor containing it (II) - Google Patents

Abstract

A compound of the formula (I), and the optically active substance, pharmaceutically acceptable salt or hydrate thereof having metalloproteinase inhiting activity.

Description

200403216 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a sulfonated amino acid derivative and a metal proteinase inhibitor containing it. [Previous technology] The extracellular matrix is composed of collagen and proteoglycan, etc., and has tissue support functions and cell function maintenance functions such as cell proliferation, differentiation, and adhesion. For the breakdown of extracellular matrix, gelatinase, stomarolex, and collagenase, which are matrix metalloproteinases (MMPs), play important roles. These enzymes are excited by physiological conditions such as growth and tissue reform. Therefore, these enzymes are considered to be involved in various pathological conditions accompanied by tissue destruction and fibrosis, namely deformable joint disease, joint rheumatism, corneal ulcer, periodontal disease, tumor metastasis or infiltration, or viral infections (such as HIV infection ). Although it is still unknown what kind of enzymes are deeply related to the aforementioned morbidity, the destruction of these enzyme-related tissues is the same. As for the metalloprotease inhibitor of amino acid derivatives, there are hydroxamic acid derivatives of amino acids (Japanese Patent Laid-Open No. Hei 6-2 5 6 2 9 3), carboxylic acid derivatives of amino acids or their hydroxamic acid derivatives ( WO 95/35276) and the like. [Summary of the Invention] Therefore, if the activity of the MMP as described above can be hindered, it can greatly contribute to the improvement of the above-mentioned pathological conditions or related to the activity, or prevent the progress, and it is desirable to develop an MMP inhibitor. In view of this, the inventors endeavored to repeatedly review the results and found that a novel sulfonamide derivative has a strong MMP inhibitory activity, that is, the present invention relates to a compound containing the following formula (I), an optically active substance, and other systems 200403216 The invention relates to a metalloproteinase inhibitor containing a compound of the following formula (i), its optically active substance, and their pharmaceutically acceptable salts' or hydrates. R1

R5-R4-R3-S02—N Human COY I R2 [wherein R1 is optionally substituted low alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or may Substituted heteroaralkyl; R2 is fluorene, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaryl compound R3 is a single bond, an optionally substituted arylene group, or a substituted heteroarylene group. R4 is a single bond,-(〇: 112) 111-,-<: 11 = (: 11-, -(: Three (:-,-<: 0-,-0: 0- > ^-, -N = N-, -N (RA)-, -NH-CO-NH-, -NH-CO -, -0-, -S-, -so2-nh-, -so2-nh-n = ch- or tetrazodiyl; R5 is optionally substituted lower alkyl, optionally substituted C3_8 cycloalkyl, May be substituted aryl, may be substituted heteroaryl or may be substituted non-aromatic heterocyclic group; R is Η or lower alkyl; Υ is ΝΗΟΗ or ΟΗ; m is 1 or 2, but Y is NHOH R2 is H]. Specifically, the following inventions a) to b), 1) to 16), and A) to C) 0 200403216 a) contain the compound of the following formula (I), an optically active substance thereof, or Their system Metal protease inhibitors that allow salts or hydrates R1 R5-R4-R3-S02-N Human COY I R2, _ [where R1 is optionally substituted low-grade, optionally substituted aryl, optionally substituted Aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; R2 is fluorene, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, may have A substituted heteroaryl or an optionally substituted heteroarylfluorenyl, R3 is a single bond, an optionally substituted aryl or an optionally substituted heteroarylene; R4 is a single bond,-(CH2) m-,- CH = CH-, -C, tri-C-, -CO-, -CO-NH-, -N = N-, -N (RA)-, -NH-CO-NH-, -NH-CO-, -Ο -, -S-, -so2-nh-, -S02-NH-N = CH- or tetrazolyl; R5 is optionally substituted lower alkyl, optionally substituted c3.8 cycloalkyl, may have A substituted aryl, a substituted heteroaryl, or a substituted non-aromatic heterocyclic group; R is Η or lower alkyl; Υ is ΝΗΟΗ or ΟΗ; when m is 1 or 2, but Y is NHOH, R2 is Η; R3 is optionally substituted arylene or optionally substituted heteroarylene; when R4 is -CO-NH- or -NH-CO-, R5 is optionally substituted aryl or may have R3 is a heteroaryl group; R3 is an optionally substituted aryl group or a substituted heteroaryl group. When R4 is a tetrazolyl group, R5 is a substituted aryl group or a substituted heteroaryl group. R3 is an optionally substituted aryl group, and R4 is a single bond. R5 is a low alkyl group, an aryl group substituted by a low alkyl group or a substituted aryl group, or a low alkyl group or a substituted aryl group. Heteroaryl substituted by aryl; both R3 and R4 are not single bonds, and R3 is not -0-] when R3 is a substituted aromatic or a substituted heteroaryl. b) The above metalloproteinase inhibitors are type IV collagenase inhibitors. If the compound of the present invention is described in detail, it can be represented by the following formula (I): R1

r5-r4-r3-so2, ^ i human COY I R2 [wherein R 1 is optionally substituted low alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl Or optionally substituted heteroaralkyl, R2 is fluorene, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted hetero Aralkyl; R3 is a single bond, an optionally substituted aryl group, or a substituted heteroarylene group; 114 is a single bond, _ (〇: 112) 111-, -〇 ^ 1 = ^^ 1-, -€ 3 0:-,-(: 0-, -0: 0-] ^ 11 -... N =, -N (RA)-, -NH-CO-NH-, -NH-CO ·, -〇- , -S-, -so2-nh-, -so2-nh-n = ch- or tetrazodiyl; R5 is optionally substituted lower alkyl, optionally substituted C3_8 cycloalkyl, 200403216 may be substituted Aryl, optionally substituted heteroaryl or optionally substituted non-aromatic heterocyclic group; RA is Η or lower alkyl; Υ is ΝΗΟΗ or ΟΗ; when m is 1 or 2 'but Y is NHOH, R2 is Η; R3 is a substituted arylene or a substituted heteroarylene; when R4 is -CO-NH- or -NH-CO-, R5 is a substituted aryl or a substituted hetero Aryl (R3 Is phenyl, when R4 is -CO-NH-, R1 is not methyl or phenyl; R5 is not 2-chlorophenyl, 4-chlorophenyl and 2,4-dichlorophenyl); R3 is It may have a substituted aryl group or a substituted heteroarylidene group. When R4 is a tetrazoleyl group, R5 is a lower alkyl group, and there may be a substituted aryl group or a substituted heteroaryl group. R3 is optional. Substituted aryl, when R4 is a single bond, R5 is a low alkyl group, an aryl group substituted with a low alkyl group or a substituted aryl group, or a substituted aryl group substituted with a low alkyl group or a substituted aryl group Heteroaryl; R3 and R4 are not single bonds, and R3 is not when R3 is an optionally substituted arylene or a substituted heteroarylene. 2). The compound of the formula II below, its optically active substance, Their pharmaceuticals allow salt or hydrate

[Where R6 is -CH = CH-, -CeC-, -N = N ·, -NH-C-0-NH-, -S-, -S02NH- or -S02-NH-N = CH ·; R7 Is optionally substituted aryl-10-200403216 or optionally substituted heteroaryl; R8 and R9 are each fluorene, lower alkoxy or nitro; R1, R2 and fluorene are the same as before]. 3) Compounds of the following formula III, their optically active substances, their pharmaceutically acceptable salts or hydrates rb R7- R10〇 > -S02-f ^

, COY ΙΠ [where Ri. _ (CH2) m-, -CO-, -CO-NH_, -N (RA)-, -NH-CO-

Or tetrazolyl; m is 1 or 2; R1, R2, R7, R8, R9, RA, and Y are the same as before, but when R1Q is -NH-CO-, R1 is not methyl or phenyl, and R7 is not 2-chlorophenyl, 4-chlorophenyl and 2,4-dichlorophenyl]. 4) Compounds of the following formula IV, their optically active substances, and their pharmaceutically acceptable salts or hydrates

iX3Ls〇2-n R2

X Y

COY

IV

[Wherein R11 is a single bond, -CH = CH-, or -C three C-; X is 0 or S; R1, R2, R7 and Y are the same as above]. 5) Compounds of the formula Γ, their optically active substances, and their pharmaceutically acceptable salts or hydrates r5W-so2-n

COY

[Wherein R1 ′ is benzyl, (indol-3-yl) methyl, (1-methylindol-3-yl) methyl, (5-methylindol-3-yl) methyl, (5-fluoroindol-3-yl) methyl, -11-200403216 (1-ethylsulfanylindol-3-yl) methyl, (1-methylsulfonylindol-3-yl) methyl , (1-ethoxyl-3-yl) methyl (such as iron ethoxymethyl), or isopropyl, R2 'is H, methyl, 4-aminoethyl or benzyl; R3' is 1 , 4-phenylene; R4 is-R5 is phenyl or hydroxyphenyl; Y is the same as above]. 6) Compounds of the formula I ", their optically active substances, and their pharmaceutically acceptable salts or hydrates

[Wherein R1 " is 4-thiazolylmethyl, (indol-3-yl) methyl, (5-methoxyindol-3-yl) methyl, 1-naphthylmethyl, 2-naphthylmethyl , 4-biphenylmethyl, 2,2,2-trifluoroethyl, 2-phenethyl, benzyl, isopropyl, 4-nitrobenzyl, 4-fluorobenzyl, cyclohexylmethyl, ( 1-methylind.late-3-yl) methyl, (5-methylindole-3-yl) methyl, (5-fluoroindole-3-yl) methyl, (pyridine · 4-yl ) Methyl, (benzimidazol-2-yl) methyl, (phenyl) (hydroxy) methyl, phenyl, carboxymethyl, 2-carboxyethyl, hydroxymethyl, phenoxymethyl, 4 -Carboxybenzyl, (benzimidazol-2-yl) methyl, (1-methylsulfonylindol-3-yl) methyl, or (1-ethoxycarbonylindol-3-yl) methyl R2 " is H; R3 " is 1,4-phenylene; R4 "is a single bond; R5 " is phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-tolyl, 4- Tertiary butylphenyl, 4-trifluorotolyl, 4-fluorophenyl, 4-methylthiophenyl, 4-biphenyl, 4-thienyl, benzoxazol-2-yl, benzoxazole- 2-yl or tetrazol-2-yl; ibid.] 7) The compound of the following formula V, its optically active substance, Drug tolerance salt or hydrate 200403216

[Where R12 is _CH = CH_ or _Ce C_; Ri, R2, R7, R8 and R9 are the same as above]. 8) Compounds of the following formula VI, their optically active substances, and their pharmaceutically acceptable salts or hydrates

[Wherein R2, R8 and R9 are the same as above, and R13 is a substituted low alkyl group, a substituted aryl group, a substituted aralkyl group, a substituted heteroaryl group, or a substituted heteroaryl group Alkyl, R14 is optionally substituted aryl or optionally substituted heteroaryl, but R13 is not methyl or phenyl; R14 is not 2-chlorophenyl, 4-chlorophenyl and 2,4-di Chlorophenyl]. 9) Compounds of the following formula VII, their optically active substances, and their pharmaceutically acceptable salts or hydrates

[Wherein R1, R2, R7, R8 and R9 are the same as above]. 10) Compounds of the following formula VIII, their optically active substances, their pharmaceutical allowable salts or hydrates 200403216

SCVhT R2

COQH

VIII

[Wherein R1, R2, R7 and R11 are the same as above]. 11) Compounds of the following formula IX, their optically active substances, their pharmaceutically acceptable salts or hydrates

[Wherein R1, R2, R7, R8 and R9 are the same as above]. 1 2) Compounds of the following formula X, their optically active substances, and their pharmaceutically acceptable salts or hydrates

[Where R12 is _CH = CH_ or _Ce C-, Ri, R7, R8, and R9 are the same as before;] 〇 [wherein R8, R9, R13, and R14 are the same as above, but R13 is not methyl or phenyl , R14 is not 2-chlorophenyl, 4-chlorophenyl and 2,4-dichlorophenyl].

-14- 1 3) Compounds of the following formula XI, their optically active substances, their pharmaceutical capacities 2 Permissible salts or hydrates 200403216 i4) Compounds of the following formula, their optically active substances, their permissible pharmaceutical salts or hydrates

[Wherein R1, R7, R8 and R9 are the same as above; I. 1 5) Compounds of formula X111, their optically active substances, their pharmaceutical allowable salts or hydrates

[Wherein R1, R7 and R11 are the same as above]. 16) Compounds of the formula χιν, their optically active substances, and their pharmaceutically acceptable salts or hydrates

[Wherein R1 'R7, R8 and R9 are the same as above].

S〇2-N COOH XTV further specifies the compounds of the present invention as follows: A)! ^, R1 ', R1 " and R13 are the above 1) ~ I6). B) R5, R7 and R14 are any one of the above and 7) to 16) which are an alkoxy group, an alkylthio group or a phenyl group which may be substituted by 1 or 2 or more. OR1, R1 ', R1 ", and R " are bonded to the asymmetric carbon configuration of R 200403216 any one of the above 1) to 16). The present invention also relates to a medicinal composition, a metalloproteinase, and a type 1v collagenase containing the aforementioned compounds i) to 16) and A) to c). The aforementioned 1) to 16) and A) to C) compounds have potent metalloproteinase inhibitory activity, and the compounds of the following formula I are particularly preferred. R1

R5-R4-R3-S〇2_N Human COY I R2 1) 111 is isopropyl, phenyl, or (〇 archer 3-methyl) methyl 'R2 is H' R3 is 1,4-phenylene R4 is -CeC-, and R5 is optionally substituted phenyl. 2) 111 is isopropyl, benzyl or (indol-3-yl) methyl, R2 is H 'R3 is optionally substituted 2,5-thiophenyldiyl, R4 is -CtriC-, R5 Is optionally substituted phenyl. 3) 111 is isopropyl, benzyl or (indol-3-yl) methyl, R2 is Η 'R3 is 1,4-phenylene, R4 is tetrazolyl, R5 is optionally substituted benzene "Alkyl" in the basic text refers to straight or branched alkyl 'such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl and the like. "Low alkyl" means a straight or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl ', third butyl, and the like. "C3.8 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. "Aryl" refers to monocyclic or fused ring aromatic hydrocarbons, such as phenyl, naphthyl, etc. 16-200403216 "Aralkyl" refers to the aforementioned alkyl substituted for the aforementioned aryl, which can be bonded to any substitutable Its location. For example, phenyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as α-naphthylmethyl), anthracene methyl (such as ^ anthrylmethyl) and the like are preferred. These aryl moieties may have any substituents. A "heteroaryl" is a 5- to 6-membered aromatic ring having one or more atoms selected from 0, and which can be fused to a carbocyclic or other heterocyclic ring, which can be bonded at any substitutable position. For example, pyrrolyl (such as -i-laloryl), indolyl (such as 2-indolyl), carbazolyl (such as 3-carbazolyl), imidazolyl (such as' imidazolyl), and pyrazolyl ( Such as 1-pyrazolyl), benzimidazolyl (such as benzimidazolyl), indazolyl (such as 3-indazolyl), indyl (eg 6-indazo), pyridyl (eg 4- Pyridyl), quinolinyl (such as 5-quinolinyl), isoquinolinyl (such as 3-isoquinolinyl), acridinyl (such as 1-acridyl), morphinyl (such as 2_ Morphinyl), daphthyl (such as 3-daphyl), pyrimidinyl (such as 4-pyrimidyl), pyrimidinyl (such as 2-pyrimidyl), oxolinyl (such as 3-B oxolinyl) ), Crotyl (such as 2 · hydrazine), quinolinyl (such as 2-quinolinyl), isoxazolyl (such as 3-isoxazolyl), phenylhydrazine (such as 3- Benzazolyl), oxazolyl (such as 2-oxazolyl), benzoxazolyl (such as 2-benzoxazolyl), benzoxazolyl (such as 4-benzoxazolyl) Oxazolyl), isothiazolyl (such as 3-isothiazolyl), benzoxazoisothiazolyl (such as 2-phenyloxaisothiazolyl), thiazolyl (such as 2-thiazolyl), benzothiazolyl (Such as 2-phenylthiothiazolyl), furanyl (such as 3-furanyl), benzofluorenyl (such as 3-phenylfluorenylfuranyl), thienyl (such as 2-thienyl), and phenylfluorenyl (such as 2-thienyl) 2-phenylfluorenyl thienyl), tetra- 11-phenyl group, etc. This • 17- 200403216 Some of these aryl moieties may have any substituents. "Heteroaryl group" refers to the substitution of the aforementioned heteroaryl group at any position of the aforementioned alkyl group These can be bonded at any substituted position. For example, thiazolylmethyl (such as 4-thiazolylmethyl), thiazolylethyl (such as 5-thiazole-2_ethyl), late methyl (such as 2-indolemethyl) Group), imidazolium methyl (such as imidazolyl methyl), benzoxazine 11 methyl (such as 2-benzoxazolium methyl), benzimidazole methyl (such as benzophenone methyl), benzene Tristriazolium methyl (such as 4- benzoxazolium methyl), phenacinoquinoline methyl (such as 2-benzoxaquinolinemethyl), benzimidazolyl methyl (eg 2_benzimidazolyl methyl) , Pyrimidinylmethyl (such as 2-pyrimidinylmethyl), etc. The aryl part of these may have any substituent. "Aryl" may be, for example, phenyl, or naphthyl, in particular, such as i, 2_ Phenyl, 1,3-phenylene 1,4-phenylene, etc. The "heterophenylene" may be, for example, thiophene diyl, furan diyl, pyridine diyl, etc. In detail, 2,5-thiophene diyl, 2,5-furandiyl "Non-aromatic heterocyclic group" refers to a non-aromatic 5 to 6-membered ring with one or more atoms selected from 0, S or N in the ring. These can be bonded at any substitutable position. Phenyl, piperidinyl, pyrrolidinyl, etc. "Alkoxy" refers to those in which the alkyl moiety is the aforementioned alkyl, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc. "Low alkoxy" means those whose alkyl moiety is the aforementioned low alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second Butoxy, tertiary butoxy and the like. "Halogen" means chlorine, iodine :, bromine and iodine. "Alkylthio" refers to those in which the alkyl moiety is the aforementioned low alkyl, such as methylthio-18-200403216, ethylthio, and the like. The substituents in the "optionally substituted alkyl group", "optionally substituted c 3 -8 cycloalkyl group" or "optionally substituted non-aromatic heterocyclic group" may be a hydroxyl group or an oxy group (such as a methoxy group) , Ethoxy), hydrogenthio, alkylthio (such as methylthio), cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halide (such as fluorine, chlorine, bromine) , Iodine), carboxyl, alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl), nitro, cyano, haloalkyl (such as trifluoromethyl), substituted or unsubstituted amino (such as methylamino, Methylamino, carbamoyl), guanidino, phenyl, benzyloxy and the like. There are more than one of these in the replaceable position. "Optionally substituted aryl", "optionally substituted aralkyl", "optionally substituted heteroaryl", "optionally substituted heteroaralkyl", "optionally substituted aryl", and The substituent on the aromatic ring in the "optionally substituted heteroarylene" may be, for example, a hydroxyl group, an alkoxy group (such as a methoxy group, an ethoxy group), a hydrogenthio group, an alkylthio group (such as a methylthio group), Cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl), halogen (such as fluorine, chlorine, bromine, iodine), carboxyl, alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl), nitro, cyanide Group, haloalkyl (such as fluorenylmethyl), aryloxy (such as phenoxy), substituted or unsubstituted amino (such as methylamino, dimethylamino, diethylamino, benzylidene) , Guanidino, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl, neo Pentyl, pentamyl), alkenyl (such as vinyl, propenyl), alkynyl (such as ethynyl, phenylethynyl), alkyl fluorenyl (such as formamyl, ethenyl, propionyl), Ethoxy (ethoxy), Fluorenylamino, alkylsulfonyl (such as methylsulfonyl), benzene-19-200403216, benzyl, azo (such as phenylazo), optionally substituted heteroaryl (such as 3-pyridyl) ), There may be substituted ureido (such as ureido, phenylureido) and so on. These can replace more than one at any possible position. [Embodiment] The compounds (la) and (lb) of the present invention can be produced by the corresponding α-amino acid of formula (χν) as a raw material 'according to the following six synthesis methods. Generally, the present invention can be incorporated according to the A method, but it can also be synthesized from B to F depending on the type. However, these are only examples of the production method of the compound (I), and the compounds (ί) produced by other methods are also included in the scope of the present invention. Method A: Synthetic method of the whole compound (I) Method B: R3 is an optionally substituted arylene group or an optionally substituted heteroarylene group. R4 is-CDC ·, and R5 is an optionally substituted aryl group or an optionally substituted aryl group. Synthesis of substituted heteroaryl compounds. Method C: A synthetic method in which R3 is a substituted arylene group or a substituted heteroarylene group, R4 is a single bond, and R5 is a substituted aryl group or a substituted heteroaryl group. Method D: Synthesis of compounds where R3 is optionally substituted aryl or optionally substituted heteroarylene, R4 is -CO-NH-, and R5 is optionally substituted aryl or substituted heteroaryl law. Method E: R3 is a substituted aryl or a substituted heteroarylated aryl, R4 is a tetra-D-diphenyl group, and R5 is a substituted aryl or a substituted heteroaryl compound law. Method F: R3 is a substituted arylene or a substituted heteroarylene s, R4 is -CO-NH-, R5 is a substituted aryl or a substituted 200403216 aryl compound Synthetic method Mody i sheep described some methods. (Method A) X R1 H2N __ ^ r5_r4_r3.s〇2.nAc〇R5-R4 ~ R3-S02-Hal R2 —— lad T < 2nd process e? NC〇NH〇H + R2 lb-1 + R5 -R4- R3-s〇2 " person

Process, R5-R4-R3-S〇4 human CONH〇Ffc? On the process 丨 R2 XVi (where R1 ~ R5 are the same as before, R! 5 is H or carboxy protecting group, R10 is hydroxyl protecting group, H a 1 is halogen).

The reaction from the compound (XV) to the compound) is a reaction in which the amine group of the compound (χν) is sulfonated (first process). After the reaction, if necessary, the carboxy protecting group is removed, and N-alkylation is performed. The reaction from the compound (^ ―: ^ to the compound (Ib-1) is a reaction in which the carboxyl group is hydroxamicated (the second process). From the compound (Ia-1) to the compound (Ib-1), the compound (Ia -l) The compound (XVI) is obtained by reacting with hydroxylamine or an acid addition salt thereof having a hydroxyl protecting group (the third process), and then subjected to a deprotection reaction (the fourth process). The sulfonation and the hydroxamic acid reaction can be performed according to It can be carried out by conventional methods. For example, an amino acid (XV) can be reacted with a sulfonating reagent such as R5-R4-R3-S02Hal (R3, R4 and R5 are the same as before, and Hal = halogen) in the presence of a base. After that, it reacts with hydroxylamine-21-200403216. Each process is described in detail below. (First process) The raw material is an amino acid of formula (XV) or an acid addition salt thereof (such as hydrochloride, p-toluenesulfonate, trifluoro Acetate) is commercially available. Others can be found in the Amino Acid Synthesis Method of Experimental Chemistry Lecture 22, 4th Edition (edited by the Chemical Society of Japan), J. Med. Chem. 38, 1689-1700 (1995 ) GaryM. Ksander et · al · etc. to synthesize. And some of the sulfonation reagents (such as sulfonium halide) are commercially available, others can be based on the new experimental chemistry lectures 1 4 volume 1 7 8 7 (1 978) »Synthesis 852-854 (1 986)» Synthesis by Tatsuo Hamada et. Al. Etc. The protected carboxyl group can be, for example, an carboxyl group of an ester (such as methyl ester, third butyl ester, benzyl ester). These protective groups The detachment can be carried out by hydrolysis in the presence of an acid (such as hydrochloric acid 'trifluoroacetic acid) or a base (such as NaOH, etc.), or by catalytic reduction (such as the presence of a 10% Pd / C catalyst). For compound (Ib-1), hydroxamation of the ester in the second process is also possible. When the solvent of the sulfonation reaction is R15 in the compound (XV), dimethylformamide and tetrahydrofuran are preferred. , Dioxane, dimethyl arylene, acetonitrile, water or a mixture thereof, but when R15 is an ester of a protecting group, a mixed solvent of other water-insoluble solvents (such as benzene, methylene chloride) and the above solvents can be used. The base of the tritiation reaction may be an organic base such as triethylamine, N-methylmorpholine, or an inorganic base such as NaOH, KOH, potassium carbonate, etc. The reaction temperature is generally from ice cold to room temperature. If the compound (la-1) R1, R2, R3, R4, R5 or R 15 has a substituent (such as a hydroxyl group, a hydrogen thio group, an amine group, Fox base) base time 'Protective Gronps in Organic Synthesis, Theodora W Green (John Wiley & Sons) and other methods to protect in advance-22-200403216' and remove this protective group at the desired stage. If R2 does not For Η ', more in dimethylformamide, tetrahydrofuran, dioxane and other solvents, add ice halides ~ 80 ° C, and add alkyl halides (such as methyl iodide, ethyl iodide, etc.) at room temperature. Aralkyl halide (such as benzyl chloride, benzyl bromide, etc.) and stirred for 3 to 30 hours, preferably 10 to 20 hours, to obtain the desired N-R2 body. (Second process) Hydroxamic acid (Ib-1) can be produced by reacting hydroxylamine with compound Ua-i) or a reactive derivative thereof. Hydroxylamine is generally an acid addition salt (such as hydrochloride, phosphate 'sulfate). , Commercially available) for reaction in the presence of a base. The base may be an organic base such as triethylamine, Ν, Ν · xylylamine, or N-methylmorpholine, or an inorganic base such as NaOH, KOH, or potassium carbonate. When the compound (Ia-1) is provided as a hydroxamation raw material, the peptide condensing reagent (such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminepropyl) carbodiimide Amine, N, N'-carbonyldiimidazole or a mixture of any of them with 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.) and the like. As the solvent, dimethylformamide, tetrahydrofuran, dioxane, dimethylarsine, acetonitrile, water, or a mixture thereof can be used. The reaction temperature is -2 0 to 4 ° C, preferably ice-cooled to room temperature, and the reaction time is 1 to 16 hours. The reactive derivative of the compound (la-1) may be an anhydride (especially a mixed anhydride), an acid halide, a fluorenyl azide, or an ester. These reactive derivatives can be produced according to a general method, and the anhydride can be reacted, for example, with compound (la-1) in the presence of a base (such as triethylamine) with an acid halide (such as ethyl chlorocarbonate). For example, the compound (la-1) is produced by reacting with a halogenating agent (such as chloramphonium chloride, sulfenylchloride). -23- 200403216 Ester can be selected from inert or active ester. The inert ester can be used in the first process compound (XV) where R5 is a carboxyl protecting group (such as methyl, third butyl, or benzyl), and the sulfonated product may be used without deprotection. The active ester may be Let compound (la-1) and carbodiimide (such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminepropyl) carbodiimide and 1-hydroxybenzotriazole Or N-hydroxysuccinimide and other active ester residues corresponding to the hydroxyl group reaction to produce. The reaction conditions for the hydroxamation of the reactive derivative of the compound (la-1) can be the same as the compound (la-1) Hydroxamic acidification at the same time. The reactions in the first and second processes can also be carried out in a single reaction tank. (The third process) The protected hydroxylamine used can be, for example, 0-benzylhydroxylamine, 0- (p-methoxybenzyl) hydroxylamine. 〇- (third butyl) hydroxylamine, etc. The reaction conditions can be the same as those in the second process. (The fourth process) The reduction of the protective group by catalytic reduction under hydrogen atmosphere or treatment with concentrated hydrochloric acid or trifluoroacetic acid. The desired compound of formula (Ib-1). The obtained compounds (la-1) and (Ib-1) of the present invention can be isolated and purified by conventional means (such as chromatography , Crystallization method, etc.) to separate purification. 24- 200403216 (Method B) 2nd process H2n ^ coor15JI1 technology,) Rl7-S (Vij meaning C00R15

XY

XVII R1,. R1 R7-CHG-R17-S02-N Human COOR15 Stomach 3 ^ Process 1 R7-CsC-R17-S02-N CO〇HH, · Price 2 XVIII 1 ^ 2 4th Process ^ r7-csc-r17- S02-N Ibr2 people

CONHOK (wherein R1, R2, R7, R5 and Hal are the same as before, and R17 is an optionally substituted aryl group or an optionally substituted heteroaryl group). The reaction from the compound (XV) to the compound (XVII) is a reaction in which the amine group of the compound (XV) is sulfonated (first process), and can be modeled after the first process of the A method. The reaction from compound (XVII) to compound (XVIII) is a Heck reaction using the halogen substituent of R17 as a stepping board (K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467 (1975), etc.) Introduction of triple bond reaction (2nd process). The reaction from compound (XV III) to compound (la-2) is the N-alkylation of compound (XVIII), etc., or the reaction of removing the carboxy protecting group (the third process), which can imitate the first process of method A. The reaction from compounds (la-2) to (lb-2) is a reaction to convert a carboxylic acid derivative to a hydroxamic acid derivative (the fourth process), which can be performed in the same manner as the second to fourth processes of the A method, and each process is detailed As described below. (First process) It can be performed in the same manner as the first process of Method A. -25- 200403216 (2nd process) Compound (XVIII) in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran, etc., with a Pd catalyst (such as 卩 (1 (? 113?) 20: 12 etc.), divalent copper reagents (such as Cul, etc.), organic bases (such as triethylamine, diisopropylethylamine, etc.), and optionally substituted aryl or The substituted heteroaryl derivative is reacted (Heck reaction) to be converted into the target compound (XVIII). The reaction temperature is from room temperature to 100 ° C, preferably from room temperature to 80 ° C, and the reaction time is 3 to 30. Hours, preferably 10 to 20 hours. If there is a substituted aryl or a substituted heteroaryl derivative that has a substituent that hinders the reaction, follow the steps of Protective GrouPs in 0rganic Synthesis, Theodora W Green (John Wiley & Sons) and other methods to protect in advance and remove the protecting group at the desired stage. (3rd process) It can be performed in the same way as the first process of the A method. (4th process) It can be performed in the same way as the 2nd to 4th methods of the A method. (C Method) R1 ·, R1 (Hal-) R17-S02- [j 人 COOR15 Rabbit 1 翌 _ R7-R17-S02 ^ Human COOR15

m XIX R1 R1

2nd system R7_Ri7_sc ^ COOH_only · 3 give process-R7-r17-s〇2-N people CONHOH R2 R2

Ib ^ (where R1, R2, R7, R15, R17 and Hal are the same as above). -26- 200403216 The reaction from compounds (XVII) to (XIX) is by replacing the carbonyl of R17 with a halogen as a stepping board and using Suzuki (MJ Sharp and V. Snieckws, Tetrahedron Lett. 26, 5 9 9 7 (1 9 8 5) etc.) to introduce an aryl or heteroaryl reaction (first process). The reaction from compound (XIX) to (la-3) is the reaction of performing N-alkylation of compound (XIX), etc., or the removal of a carboxy protecting group (second process), which can be performed in the same manner as the first process of method A. The reaction from compounds (Ia-3) to (lb-3) is a reaction in which a carboxylic acid derivative is converted into a hydroxamic acid derivative (the third process), which can be performed in the same manner as the second to fourth processes of the A method. Each process is detailed below. (First process) Compound (XVII) is palladium catalyst (such as Pd (Ph3P) 4, etc.) in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran, and a base (such as potassium carbonate, carbonic acid). In the presence of calcium, triethylamine, sodium methoxide, etc., phenylboronic acid and the like may be derived from optionally substituted aryl groups or substituted heteroaryl groups having B (0H) 2 (other than B (Et) 2 etc.) groups. Physical reaction (Suzuki reaction), it can be converted into the target (XIX). The reaction temperature is from room temperature to 100 ° C, preferably from room temperature to 80 ° C, and the reaction time is from 5 to 50 hours, preferably from 15 to 30 hours. If a substituted aryl or a substituted heteroaryl derivative has a substituent that hinders the reaction, it can be protected in advance by methods such as Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. Remove the protecting group at the desired stage. (Second process) It can be performed similar to the first process of method A. 200403216 (3rd process) Can be performed in the same way as the 2nd to 4th process of A method (D method) R1

h2n coor1 2CV The first meaning 扉 (〇 和) Ft17-S02A person C00R15 second lease ΣΣ (H2N-) R17-S〇2- [j 人 COOR15 Nest 3 — 癀 > R7 一 客 一 Ν— # 一 s 〇2-N 人 COOR15 Η Η Η,

XXI XXII 箩 -1§Select + r7-C-N-R17-S02-N ^ C00H — H q2

la-4 R R1 Ο Ϊ -C-N-R17-S02 " N CONHOH H ^

Ibz4 (wherein R1 to R5 are the same as before, R15 is a H or carboxy protecting group, a hydroxyl protecting group, and HaL is a halogen). The reaction from compound (XV) to (XX) is a sulfonation reaction (first process) of the amine group of compound (χν), which can be performed according to the first process of method A. The reaction from compounds (XX) to (XXI) is a reaction in which the nitro substituent of R17 is reduced to an amine group (second process) 'can be carried out under the reaction conditions of a catalyst reduction method or iron hydrochloride or tin hydrochloride. The reaction from compounds (XXI) to (XXII) is a reaction in which an amine group of R 17 is used as a stepping board to form an amidine bond (3rd process), which can be carried out in a manner similar to the commonly used amidine bond formation reaction. The reaction from compound (XXII) to (la-4) is the reaction of compound (XXII) to -28- 200403216 N-alkylation, etc., and the removal of the carboxy protecting group (the fourth process), which can imitate the first process of method A get on. The reaction from compounds (Ia-4) to (ib_4) is a reaction in which a residual acid derivative is converted into a hydroxamic acid derivative (the fifth process), which can be performed in the same manner as in the second to fourth processes of the A method. Each process is detailed below. (First process) It can be performed in the same manner as the first process of Method A. (Second process) Compound (XX) is present in a solvent such as methanol, ethanol, ethyl acetate, acetic acid or the like (Pd-C, Pt02, Ruanlai Nickel, etc.) under a hydrogen atmosphere, normal pressure or pressurized conditions. The reaction was performed to obtain the target compound (XXI). The reaction temperature is from ice cold to 80 ° C, preferably from room temperature to 50 ° C. The reaction time is 1 to 10 hours, preferably 2 to 5 hours. (Step 3) The compound (XXI) is tested in solvents such as dimethylformamide, tetrahydrofuran, dioxane, dimethylene®, acetonitrile, xylene, toluene, benzene, and dichloromethane (such as diethyl ether). In the presence of amine, N-methylmorphine, osmium carbonate, etc.), it may be derived from an optionally substituted aryl group or an optionally substituted heteroaryl group having an acid halide functional group (other than an active ester) such as benzyl chloride. Reacts to convert to the target (XXII). The reaction temperature is ice cold ~ 100 ° C, preferably room temperature ~ 60 ° C. (: The reaction time is 3 to 30 hours, preferably 10 to 25 hours. (Fourth process) It can be performed imitating the first process of the A method. (Fifth process) It can be performed imitating the second to the fourth method of the A method. -29- 200403216 (Method E) Η

XY R1 R1 (OHO) R17-S02 $ person COOR15 pens each R7H_N = ^-R17-SOq person COOR1

XXIV

XXV R1 筮 4 靱 β ^ a 11 :; 5th process-R7-N, ^ -Rt7-S02, COOR1 gas ---

N H

XXVI N = N 丄 sensitive β system N = N 丄 -κ / r17 — S02, N human COOH — ~ R7 — N ’, > R17-SCVN human CONHOH N R2 N R2

UA IbiS (where R1, R2, R7, R15, R17 and Hal are the same as above). The reaction from compound (XV) to (XXIII) is a reaction in which the amine group of compound (XV) is sulfonated (first process), which can be performed according to the first process of method A. The reaction from compounds (XXIII) to (XXIV) is a reaction in which the vinyl substituent of R17 is converted into an aldehyde (the second process). The reaction from compounds (XXIV) to (XXVI) is a reaction for constructing a tetrazole ring (processes 3 and 4). The reaction from compound (XXVI) to (la-5) is the reaction of compound (XX VI) to N-alkylation, etc., and the removal of the carboxy protecting group (5th process), which can be performed in the same manner as the first process of method A. The reaction from compounds (la-5) to (Ib-5) is a reaction in which a carboxylic acid derivative is converted into a hydroxamic acid derivative (the sixth process), which can be performed in the same manner as the second to fourth processes of the A method. Each process is detailed below. (First process) -30- 200403216 It can be performed in the first process of A method. (Second process) Compound (XXII) is added with ozone in solvents such as dichloromethane, ethyl acetate, and methanol to form odor oxides, followed by the addition of zinc-acetic acid, triethyl phosphate, or dimethylphosphine in the same system. Reduction treatment, and conversion to the aldehyde derivative (compound (XXIV)) (reduction treatment can also add catalyst hydrogen). The reaction temperature is -1 0 ° C to room temperature, preferably -78 ° C to ice-cold, and the reaction time is 0.5 to 10 hours, preferably 1 to 3 hours. (First process) Compound (XXIV) is reacted with benzenesulfonylhydrazine in a mixed solution of a solvent such as tetrahydrofuran and diethyl ether and a solvent such as methanol and ethanol to be converted into the target compound (XXV). The reaction temperature is ice-cold to 80 ° C, preferably room temperature to 50 ° C, and the reaction time is 3 to 30 hours, preferably 10 to 20 hours. (Fourth process) An aryl group, such as aniline, which may have a substituted aryl group or a substituted heteroaryl derivative, is dissolved in an alcohol (such as ethanol) -water mixture, and the temperature in the system is -20 to 0 ~ 10 ° C, preferably 0 ~ 5 ° C, into diazonium salt in diazotizing agents such as concentrated hydrochloric acid and aqueous sodium nitrite solution. The reaction time is 5 minutes to 1 hour, preferably 10 to 30 minutes. Then inject it into a pyridine solution of the compound (XXV), and react at -3 0 ~ 50 0 t :, preferably-1 5 ° C ~ room temperature for 1 ~ 10 hours, preferably 2 ~ 5 hours to transform into the target substance (XXVI). . If the substituted aryl or the substituted heteroaryl derivative has a substituent that hinders the reaction, it can be protected in advance by methods such as Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. Removal of protecting groups at the desired-31-200403216 stage. (Fifth process) It can be performed similar to the first process of method A. (Sixth process) It can be performed similar to the second to fourth processes of A method. (F law)

R1 R7-〇C-R17-S〇2-N Human COOR15 Η Η 2 Η XXVII R1

(OHO) R17-S02- ^ j Person COOR15 Roe 1 Manufacturing XXIV R1 3rd Process ------ p.

2nd split, β X

--R7-c = c-r17-so2-n C〇OI Η H ^

Ia, 6 R1

R7-〇OR17—S02-N Eight CONHOH Η H lb-6 (wherein R1 to R5 are the same as before, R15 is H or carboxy protecting group, R16 is hydroxy protecting group, Hal is halogen). The reaction from compounds (XXIV) to (XXVII) is based on the aldehyde of R17 as a stepping board, and the conventional Wittig reaction (G. Wittiget.al., Chem. Berr. 8 7, 1 3 1 8 (1 9 5 4) ) Conditions, etc., the reaction of introducing an aryl or heteroaryl group via an intermediate double bond (first process). The reaction from compound (XX VII) to (U-6) is the reaction of performing N-alkylation of compound (XXVII), etc., and removing the carboxy protecting group (second process), and it can be performed in the same manner as the first process of method A. The reaction from compounds (la-6) to (lb-6) is a reaction in which a carboxylic acid derivative is converted into a hydroxamic acid derivative (the third process), which can be performed in the same manner as the second to fourth processes of the A method. -32- 200403216 Each process is detailed below. (First process) Compound (XXIV) is dissolved in solvents such as toluene, xylene, tetrahydrofuran, diethyl ether, dimethylformamide, etc. to-loot: ~ room temperature, preferably -78 t ~ under ice-cooling Ph3P = CHPh and other substituted aryl groups or alkynides of substituted heteroaryl derivatives can be prepared by the method and stirred for 1 to 20 hours, preferably 1 to 5 hours, can be converted into the target (XXVII). If the substituted aryl or the substituted heteroaryl derivative has a substituent that hinders the reaction, it can be protected in advance by methods such as Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. Remove the protecting group at the desired stage. (Second process) It can be performed similar to the first process of method A. (Third process) It can be performed in the same way as the second to fourth processes of A method. The term "compounds of the invention" also includes pharmaceutically acceptable salts or hydrates thereof. Such as alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, salts with organic bases and amino acids, or with inorganic acids (hydrochloric acid, osmium bromide, phosphoric acid, sulfuric acid, etc.), And organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. salts. These salts can be formed by conventional methods. The compounds of the present invention are not limited to specific isomers. Including all possible isomers and racemates. The compounds of the present invention have excellent metal-33-200403216 protease inhibitory properties, as shown in the experimental examples described below, especially MMP inhibitory activity and matrix decomposition. Therefore, the compounds of the present invention are responsible for It is effective for diseases such as MMP and its similar enzyme TNF-α-converting enzyme, etc. Specifically, it can be used to prevent deformity arthrosis, joint rheumatism, corneal ulcer, periodontal disease, tumor metastasis or invasion, viral infection (such as HIV infection), occlusive arteriosclerosis, atherosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, scleritis Multiple sclerosis, open-angle cataract, retinopathy, proliferative retinopathy, angiogenic green cataract, pterygium, keratitis, vesicular epidermal detachment, xerobia, diabetes, nephritis, neurological disease, gingivitis , Tumor proliferation, tumor angiogenesis, eye tumors, angiofibromas, hemangiomas, fever, bleeding, coagulation, cachexia, loss of appetite, acute infection, shock, autoimmune disease, malaria, clonal disease, meningitis, and Gastrointestinal ulcers. When the compounds of the present invention are administered to humans for the prevention and treatment of the above-mentioned diseases, they can be administered orally as powders, granules, tablets, capsules, nine, liquids, etc., or as injections, troches, transdermal absorbents, inhalants, etc. Non-oral. In addition, an effective amount of the compound is formulated as needed with excipients, adhesives, wetting agents, dispersing agents, smoothing agents and other pharmaceutical additives to form a pharmaceutical preparation. If it is an injection, it can be used with appropriate The carrier is sterilized together to make a preparation. The dosage varies depending on the state of the disease, the route of administration, the age of the patient or the weight of the patient, and ultimately depends on the physician. Generally, it is 0.1 to 100 mg / kg / day when taken orally by an adult, preferably 0.1 to 1 mg / kg / day, and this is administered once or in a fraction of -34-200403216. The following examples and experimental examples describe the present invention in detail. The abbreviations used in the examples are as follows: p-TsOH: p-toluenesulfonic acid DMOS: dimethylsulfene Me: methyl tBu: third butyl Example 1 (Method A)

ξχ) ·

SCVN Eight CO〇H Η la small 1

p S02, eight CONHOH Η, (R)-(+) -phenylalanine (compound (XV-1) 1.65 g (10 mmol) was suspended in dimethylformamide and water 3 5 m 1, and Add 2.78 ml (20 mmol) of triethylamine while stirring. Then add 10 ml of 2.52 g (10 mmol) of dimethylformamide in 5-minute portions. After stirring at the same temperature for 2 hours, force 1 -Hydroxybenzotriazole hydrate 1.35 g (10 mm 〇1), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 2.1 g (11 mmol), hydroxylamine hydrochloride Salt 3.47 g (50 mmol) and triethylamine 7 ml (50 mmol), stirred at room temperature for 16 hours, and poured into water. Extracted with ethyl acetate, followed by 2N hydrochloric acid, 5% sodium bicarbonate water and water Washed, concentrated under reduced pressure • 35- 200403216, and then subjected to silica gel column chromatography (chloroform / methanol = 40/1 ~ 20/1) to obtain 1.70 g of a foamy residue (compound lb-1-1). Yield 4 3 % Melting point 1 6 9-17 0 ° C.

Elemental analysis 値 (%) C21H2 () N2 04 S Calculation 値 · C; 63.62 Η; 5.08 Ν; 7.07 S; 8.09 Experiment 値: C; 63.61 Η; 5.12 Ν; 6.98 S; 8.06 IK v max (cm ~ 1) (Nujol): 3365, 3295, 3266, 1674, 1320, 1159 NMR (5 ppm) d 6 -DMSO: 2.61 (dd, J = 8.6, 13.4Hz, 1H), 2.80 ( dd, J = 6.0, 13.6Hz, 1H), 3.80 (m, 1H) ► [a] £ > ··· 18.5 ± 1.2 (c = 0.603%, 25t :, DMSO) Example 1f Compound Ib-1- 1 ^ Synthesis p-TsOH z H2N ^ COOCH2Ph 1st process

XV-Γ

Process 1 * 36-200403216 To a solution of (R) -phenylpropylaminobenzyl p-toluenesulfonate (compound XV-Γ) in 2.5 ml (5.85 mmol) in 60 ml of dichloromethane is added 1.8 ml of triethylamine under ice cooling. (12.87 mmol) and 1.6-diphenylsulfenyl chloride (1.64 g). After stirring at room temperature for 2 hours, sequentially with 2N-hydrochloric acid,

5% sodium bicarbonate water and water were washed, concentrated under reduced pressure, and then subjected to silica gel column chromatography (chloroform / methanol = 4 0/1 to 20/1), and recrystallized from dichloromethane-hexane to obtain a compound Ia- 1-l '2.32 g, yield 84.1%, melting point 130-13 1 ° C. Elemental analysis 値 (%) C28H25N04S Calculated 値: C; 71.32 Η; 5.34 Ν; 2.97 S; 6.80 Experimental 値: C; 71.05 Η; 5.41 N; 3.00 S; 6.81 IR v rnaxicm ^ 7 1) (Nujol): 3352, 1732, 1341, 1190, 1163 NMR (< 5 ppm) (CDCl 3): 3.06 (d, J = 5.8Hzl 2H) t 4.30 (dt, J = 6.0f 9.0Hz,! H) r 4.89 (s, 2H), 5.12 (dp J = 9.0Hzt 1H), 6,98-7.81 (m, 14H) [a] D: -16 · 4 soil Ll (c = 0.506%, 25 * 0, MeOH ) 2nd process

The compound Ia-1-1 ′ obtained in the first process was dissolved in 2.28 g of methanol / ethyl acetate = 1/1, and hydrogenated with 10% Pd-C 2 00 mg for 25 minutes, and then the catalyst was filtered off. Concentrated under reduced pressure and recrystallized from dichloromethane / hexane to obtain Compound Ia-1-l "1.83 g, yield 99.1%, melting point 1 46-1 47 ° C. Elemental analysis 値 (%) C21H19N04S calculation値: C; 66.12 Η; 5.02 Ν; 3.67 S; 8.41 Experiment 値: C; 65.97 Η; 5.06 Ν; 3.61 S; 8.48 200403216 IR v max (cm ~ 1) (NujoI): 3408, 3305, 1751, 1325, 1161, 1134NMR (δ ppm) (CDCl 3): 2.97 (ddJf7.0, 13.8Hz, 1H), 3.14 (dd, J = 5.2, 14,0Hz, 1H) , 4.13 (m, 1H), 7-03-7.78 (m, 14H) [a] D: -4,0 to 0.4 (c = 1.000o / o, 25t :, MeOH) The third process will be obtained from the second process Compound I a-1-1 '' 1.0 g (2. 6 2 mm ο 1) was dissolved in 20 ml of dichloromethane, 0.33 ml (3.93 mmol) of chlorchloramine and 1 drop of dimethylformamide. Stir at room temperature for 1 hour. After concentrating under reduced pressure, dissolve in 10 ml of tetrahydrofuran. In addition, 911 mg (13.1 mmol) of hydroxylamine hydrochloride is mixed with 10 ml of tetrahydrofuran containing 1.54 g (18.34 mmol) of sodium bicarbonate and 10 m 1 of water. In the cold After stirring for 5 minutes, add the tetrahydrofuran solution of the above acid chloride. After stirring for 30 minutes, pour it into water. Extract with ethyl acetate and wash with 5% sodium bicarbonate water and water in order, and concentrate under reduced pressure to obtain a residue. 969 mg (Compound Ia-1), yield 93.3%. In the fourth process, 2.0 g (5.24 mmol) of the compound Ia-1-l obtained in the second process was dissolved in dimethylformamide 20 m 1, Then add 0.7 g (5.24 mmol) of 1-hydroxybenzitriazole hydrate, 2.91 ml (26.2 mmol) of N-methylmorphine, 1-ethyl-3- (3-diisopropylamino) carbodiimide salt Acid salt (Smmol), then 1.67 g (10.48 mm) of 0-benzylhydroxylamine hydrochloride was added, stirred at room temperature for 6 hours, and then poured into water. It was extracted with ethyl acetate and washed with 2N hydrochloric acid, 5% sodium bicarbonate water and water sequentially, concentrated under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate / hexane = 1/1), followed by dichloromethane. / Hexane recrystallized,

2.04 g of compound XVI-1 was obtained, yield 80%, melting point 171-1 73 ° C -38- 200403216 elemental analysis 値 (%) c28h26n2o4s Calculated 値: C; 69.12 Η; 5.39 Ν; 5.76 S ; 6.59 Experiment 値: C; 68.85 Η; 5.46 Ν; 5.76 S; 6.78 IR v max (cm-1) (Nu: jol): 3248f 1661, 1594, 1333, 1163 NMR (< 5 ppm) (CDCl 3): 2.85-3.60 (m, 2H), 3.86 (m, 1H), 4.77 (ABq-

Apart, 1H), 4.82 (ABq-Bpart, J = 11.4Hz, 1H), 5.00 (m, 1H), 6.95-7.70 (m, 19H) — [cr] D: · 40 · 2 ± l'6 (c = 0.505%, 25t :, DMSO) In the fifth process, 1.97 g of the compound XVI-1 obtained in the fourth process was dissolved in 60 ml of a methanol / ethyl acetate = 1/1 mixed solution, and 200% of 10% Pd-C was hydrogenated to 3.5. After hours, the catalyst was filtered off, concentrated under reduced pressure and recrystallized from dichloromethane / hexane to obtain 1.35 g of compound Ib-1-l in a yield of 84.4%. Examples 2 to 9 1 The compounds of Tables 1 to 22 were synthesized in the same manner as in Example 1. -39- 200403216 HOHNOO ^ HisiQ: Ή * ΝΜΕ (δ ppm) dc-DMSO 2.87 (dd, J = 5.6.14 · 2Ηζ · 1 H > · 2.98 (dd, J = 8.4 (H.2Hz, 1H), 4 .〇2 (ddlJ = 2.2. 8.6Hz, 1H), 7.24 (d, J = 2.0Hzi1H), 8.83 (d, J = 2.2H2jH) 2.72 (ddfJ = 7.2t13.8Hz, 1H), 2.97 (ddl 7.0, 14.8Hz, 1Η), 3.81 (Γη, 1Η), I 3.12 (dd, J = 10.3, 14.3Hz, 1H), 3.89 (dd, J = 3.3, 13.5Hz, lH). 4.20 (m, 1H), 5.90 ^ (brs, 1H) 2.67 (dd, J; 9.2,13.1Hz, 1H), 2.84 (dd · J = 5.3,13.5Hz, 1 H), 3.82 (m, 1H) _-.__ — '. i- 2.2-2.7 (mt2H), 3.99 (U = 7.0Hz, 1H) 1.68 (mf2H), 2.37 (m, 2H) f 3.64 (t, J = 6.9Hzt1H) I ---------- 2.61 (dd , J = 9.4l13.8Hzl1 H), 2.78 (dd, J = 6.0 · 13.8HZ · 1 H) 3.78 (m, 1 H), 7.43 (d, J = 8.2Hzf2H) 17.60 (d1J = 8.2Hz, 2H ) l IR (v cm-1) Tao 3258, 1650, 1377, 1348,1163 (Nu) ol) 3403,3386,3265,1673,1320,1162 (Nujol) I rC σ > CO σ > 〇) CD to C 〇T- N OJ CM CVJ C: CO T- 3262,1663,1322, 1157, ^ 4 3265,1676,1642, 1337,1161 (Nujol) 3403,3261,1669, 1321,1160 3700-2200brt3264, 1635, 1342,1164, b (decomposition point) m.pt. (* C) i 173 > |! I 203-206 I 124-126! 139-141 I 167-169 172-173 r144 * 146 1〇fiE * pc: s; S 1¾ 20 a: Φ CD S々N v = z-ch2 · 〇 ^ £ 4 〇x / HQ 8 £ CO ch2- cf3ch2- < Q > -CH2CHr < 〇KHr Example No. CO ιΛ COCO σ >

-40- 200403216 HOHNQo ^ HNCVJosobla: Ή-ΝΜΕ (ΰ ppm) db-DMSO 2.60-2.82 (m, 2H), 3.84 (m, 1H), 7,00-7.18 (m, 5H), 7.62-7.80 (m , 4H), 2.70-2.93 (m, 2H), Z82 (s, 6H) t 3.75 (m, 1H), 0.71 (dJ = 6.8Hz, 3H), 0.74 (dfJ = 5.4Hz, 3H), 1. 73 < m, 1H}, 1.73 (m, 1H) .3.22 (m, 1H); 82 (s, 3 H) f7.05 (dJ = 9.0Hz, 2H), 7.69 (dJ = 9.0H2.2H) 2.80 ( dd, J = 10.0,13.8Hz, 1 H), 2.92 (dd, | J = 5.0,12.8Hz, 1 H), 3.90 (ddt J = 5.4t 9.6H2.1H), ί 2.62 (dd, J = 9.9 , 13.5Hz JH) 2.78 (ddJ = 5.8f 13.0Hz, 1H), 3.77 (t, J = 6.2Hzf 1H), 0.50-1.62 (mf13H), 3.56 (t, J = 7.4Hz, 1H) 2.71 (dd, J = 7.9,14.2Hz, 1 H), 2.94 (dd, 丨 J = 6.9,14.2Hz, 1H) 3.57 (s, 3H) .3.83 (dcU = 7.0,7.4Hz, 1H) 2.25 (5 , 3 ^, 2.67 ((1 (^^ = 7.5,14 ^ 2, 1H), 2.95 (dd, J = 7.7 · 14.6Hz · 1H) · 3.81 (C3 (1, J = 6.2J 4.2Hz, 1H) IR (v cm-1) (KBr) 3600-24005 ^ 3257, 1743,1721,1323,1132. _I CD s? §8 8S 3268,1632,1598, 1336,1162 < DG r- CD in -t- r— cvTcvf iD CM o rr to 廿 CM eg CO! 3258,1669,1509, 1322,1157, 3278.2920,1632, 1337, / 1161 3272,1631,1332, 1161 S CO Τ CD 5 * 〇 > O l〇々r-CO insect point (decomposition point: rn.pt.CC> 116- 118 _I 91-92 178-179 i 184-185 128-130 I ί 165-166 j 172-173 I 144-146 * P3 to a: ο χΠ Q- (CH3) 2NH ^ H3co ^ Q ^ Q > -CH2 -_ I £ o ό (CH3) 2CH- — 〇2N ^^ CH2- R〇KH2- C ^ CHr I ί o! H3cO—iLcH2 · Example 'No. 1 ο rH • -H r—4 CO r— H • -H \ nr—1 CD rr— < -41- 200403216 3 Table HOHNOOOHNCNIocnQ & la:

SSSOHJAIK.HI (Η icvr8co- {H 'ΝΗ3 · ηοί. 9 = `` • pp) 06CNJ- (mNHO > roco " r * pp? Jzci • × Τ—ΝχΟ · 卜 = 3) sc0-xlNH8cvir9loHr • pp) 6zcvj- { HnNH BU · ει · 8σ > " Γ · ρρ) 89οί XCNJNX inch α5Η 「-ρίο6κχ3ΝΗ0οο =「 · ρ) 08 · bu- (HCVJ-et ^ tztvxwecoeo-cvicvico (ΗΙ.ΝΗ9 · ε = τ · ρ) ι6ν ( ΗΙ.ΝΙΗ9 · ε " Γ · ρ) 98 · ε χι € 0ΚΓ6Όι · (Ηι · 5) οο6 · Β 乂 Η t · 25 · 6 = Γ · Ρ5ΤΖ € 0 · χ ^ Η ^; 64 · P) 008. Inch Q9 > 8nmN · 9 · ζη3) ζζ · ε · χιΜΗ9 · ε i.Co * ρρ) ε6 · 3-ΙιΝΗ5 · ε'9 · ζ = φχ5ρ) 69 · 3 Q〇c? OnHlwHS · 9 < ο = `` · ρρ ) /8.ε·χτ-ΝΙΗ9.εΓ9·9=Γ * op) 96CHxlNHs.el-co.co = r-pp) inch zcvi §! ≫ I §1 (1HI ii SU-C32 Cvi6s5z9525 σ > ζει o9Hco6sl < o8l.co 09ι · ι · 93εια399Ι. cvrscvicoIJ-qoos-oozc • οϋ9τ— 「86ει sucots · inch 6SIσ) 99ιιη.εε ^ §ε

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HOHNO0, HNcvlocoo & ly! H-NMR (5 ppm) dfi-DMSO 2.60 (ddlJ = 9.0, 13.8Hzl1H) l2.79 (ddt J = 9A13.8Hz, lH) 3.76 (m, 1H) III! Mi σί X 〇〇Λ n " X 〇 * σ X CM 05 < 〇T- < n Ό C4 ^ fod CM 1 1 3.29 (dd, J = 5.7, 10.7Hz, 1H) t3.43 (dd, 8.4, 10.7 Hz, 1 Η) 3.62 (γπ, 1H), 7.85 (A 2B 2q.J = 8.7Hz, 2H), 7.88 (A2B2q.J = 8.7Hz. 2H), 7.98 (d, J = 7.8H2,1H) .10.61 (s.lH) 2.69 (dd, J = 7.6f13.5H2t1H), 2.93 (dd (J = 7.6 > 13.5Hz, 1H) l3.77 (tiJ = 7.6H2l 1H), (CD3OD) 1 1 2.66 (ddtJ = 7.5l13.4Hz, 1H), 2.96 (ddl J = 7.6_M'2Hz, 1Hh3.81 (n〇H) 1! W IR (vcm-l) (KBr) 3700-2200 (br), 3362, 167〇, 1590,1336,1152! 3700-2200br, 3372,1674, 1531,1348,1310,1161 _i 1 i I 3700-2400 (br), 3392, 1667,1320,1161! ^ 3700.2200 (br) t1671, 1329,1163 i 3401,3260,1673, 1316,1165 melting point fen solution i m.pt.CC) 63-65 I 70-71 tr 192-193 69-70 1 160-162 > * Pi Ct5 Φ UL Φ 1 g Qch2-! HOOC-CHr 1 hooc-ch2-ch2- HOCHr, ^ ~ y-CH2〇CH2 > HOOCH ^^ CHr 〇 / = xz ο Example No. I CO Cvj 142 Ol 2 8 2 (Ji CM o CO 9- ^ CS3 CO CO -43- 200403216 5 Table (§ .

HoHMOOOHNcviococ & lcr

lH-NMR (5 ppm) (k-DMSO 1 2.84-3.21 (m, 2Hh4.29 (m, 1H) 丨, &) IR (v cm-1) (KBr) 1 3700-2400 (50 * 1672, 1443,1327,1094 Melting point (decomposition ^ m.pt.〇3) 1 141-145 * S 30 Qi | μ γ CD f1 〇xz 5 x " Example No, CO to CO -44- 200403216

6rtl) HoooeH ^ OS.Bo: Table T Ν-NMIL ((5 ppm) (U-DMSO 2.95 (dd, J = 9.0, 14.0H2, 1 H), 3.12 (dd, ϋ = 5.4 · 14 · 0Ηζ · 1Η ), 4.13 (ηιΐΗ), 7,29 (d, J = 2.0Hzti H), 8.34 (dJ = 8.6Hzt t H). 8.88 (dJ = 2.0Hz, 1 H). 12.79 (br.1 H} 2.88 (dd, J = 8.0, 14.0Hz.1H), 3.09 (dd, J = 6.0 # 14.0Hztl H), 3.91 (m, 1 ^, 8.23 (m, 1 H) (10.79 (s , 1 H) tl 2 J0 (br *, 1 H) 2.75-3,06 (m, 2H), 3.69 (s, 3H). 3-90 3.17 (dd, J = 7.4,13.8Hz, 1H), 3.57 (dd, J = 5A13.9Hz, 1H), 3.80 (t, J = 5.6Hz, -1Η). 8.11 (^^ 7.4Η2% 1Η) 2.77 (dd, J = 9.7,13-7Hz.1H), 3.03 (dd, 丨 J = 4.9,13 · 3Ηζ · 1H), 3.93 (m · 1 Η) · 38 · (d, J = 8.8H2,1H) I ~ I 2.40-2.90 (01,2 ^, 4.05 ( 01,1H), 8.51 (d, J = 9.〇H; 1H > J3.2 (br, 1H) 1.83 (towel, 2H), 2.52 (m, 2H) 3.70 (m, 1H), 8.32 (d, J = 9.0Hz, 1H) 2.86 (m1lH) r2.87 (sl6H) I2.98 (dd, J = 5.1,13.8Hz, 1 H), 4.15 (m, 1 ^, 5.54 i) IR (v cm-1) .a < Br) 3276l2503br, 1897br, 1724,1344,1170 (Nuj〇l) 3386,3305,1747,1363, 1323,1161,1135 (^) 01} 2400-3700 (br), 1734, 1484,1327,1160 3446,3065,1594,1397, 1303,1154,1094 3184,1723,1337, 1317,1156 ^ 3276,1706,1344, 1260,1165 / < D CM CO crT 〇 > C O 00 h- o σ > of co in CM CO CO CO ca co of CO OO) ρ CM bu CQ CO ΤΟ ui O CNJ CVJ bu CM -r- melting point (decomposed black 159-161 227-229 181-189 198 -200 213-215 176-177 153-156 I 103-105 * Dd 33 Cd. Contains g (CH3) 2NH ^ j) S ^ N ^ -ch2. I f1 〇xH ox / H \ ·.% CO 丨 ch2 Q〇ch2- CF3CHr < ^-ch2ch2- o Example No. CJ cn 00 1-tr- »-45- 200403216 Table 7

-46- 200403216 8 Table (Bo HOoa ^ HNOJosooa: T cc OSNaip sCIdsoi.Hl xtNxCVJco = Γ · σ) ε lln · (H 1NH3C04. P) 0 "Inch (H「 s. 」Qqe'xlNHK6 = Γ · ρ) § € 0 · χι · ΝΗΚ6ΗΓ * ρ) ττ6. Inch • (huNH inch · 9'9,9 = 「· ορ) ε9 · ε (Η ι · 25 · 9 LCNJ * 9 = rpp) s inch cvi • {5 · Ε) § &ό; {δ NHc \ JN = 3crCVJcvj * (mNH inch · CQLo < our • ppuco-: xM-HrHo; 7. = r-pp) 89 ·· »-(ΗΙ.ΝΗZ.8 = Γ · ρ) 9οα5 • (Η l-UJoconxT-'NHeCNil.-inch · 9 " Γ • pp) ssriItNH6CNilo: 9 = rTrPHtnco (huNH 5 = rp ^ cocd * (HCVJ < n) 6co.inch, {H ' E) s V (Η ΓZOΗ6 · 6Κ · 54 • ppo9co- (HLNH6.6-oo.t ^ r * pp) t79co (Hlw./qmcocvi'xιΝΗΟ·6=Γ·ροτί··8 * Xι * Ε) 96 Ε_χτ ~ ΝΗκε 1 «: inch 4 -pp) sco-xlN engineering ο『 B CJ > = r-pp) 5cvi πθϋ I sf (I!) HI sii Ο45κιο · οι- < ΝεΛι_9 ^ ειηεεε (oinN) su InCNJcoKcof 9ιεΓΟ 960llnlou coOJsCVJszrscoco solcnsu · 9εει. · 6οζτ- · ΌZOς \ ίε cvf9u > 3c3r8CMacvr6CVJccoJns nsec εΒοοζοοο33 suococtcoTccccczc} 003⁄2

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Yuan cable analysis 1 I C24H22N205S.a5H20 Ca (c. C: 62.73 H: 5.04 N: 6.10 S: 6.98 Foun.C: 62.75 H: 5.08 N: 6.31 S: 7.05 C24H22N2O5S * 0.8H2O Calc. C: 62.00 H: 5.12 N: 6.03 S: 6.90 F〇un.C: 62 * 03 H: 5.06 N: 6.08S: 6.82 I 1 I C17Hi9NO4S * 0.1CF3COOH Calc. 0: 59.99 H: 5.58 N: 4.06 5: 9.30 Foun.C: 60.37 H: 5.74 N: 4.13 3: 9.76 1 and) IR <v cm-1) * (KBy) 1726,1354 1326,1161 1732,1594 1404,1155 1607,1594 1294,1153 .1724,1594 1326,1159 1685, 1349 1166 1 1725,1599 1372,1173 / 1745,1653 1391,1147 1714,1594 1334.1166 Melting point (decomposition ^ m.pt.CC) j &gt; 145 I 188-190 90-93 149-152 1 104-107 I i 167-169 i; 155-157 * I [* price 30 oc 丨 · H3CO X IL | H3CS-〇 ~ 〇 · I CM δ JQ COOC2H5 〇tn1.h £ 0 rzH Q ◦ F = xz Q 〇ίι〇Η2 -ci〇H2- (CH3) 2CH- Example No. • ^ D CO BU cn CO 0 CO 0 1. ^ Γ0 n4 TO -49- 200403216 1 1 Table (B1) ΗΟΟΟ ^, Η ^ ΟΓα: C2tH27NO4S.0.3H2O Calc. 0: 63.87 H: 7.04 N: 3.55 S: 8.12 Foun.C: 63.84 H: 6,86 N: 3.42 S: 8.01 C23H23N04S.a3H20 Calc. 0: 66.58 H: 5.73 N 3.38 S: 7.73 Foun.C: 66.45 H: 5.52 M: 3.24 2: 7.56 I 1 4 Ct7H18FN04S Calc. 0: 58.11 H: 5.16F: 5.41 N: 3.99 3: 9.12 F〇un.C: 58.11 H: 5.17 F : 5.86 N: 3.92 S: 9.69 I i C27H23NO4S * 0.7H2〇Calc. 0: 68.98 H: 5.23 N: 2.98 S: 6.82 Foun.C: 69.08 H: 5.09 N: 2.91 S; 6.73 1 5) IR ( v cm-1) | a®r) 1724,1340 1328,1167 σ &gt; o N v- r— »— CO CV .N CO Y— T— in co T— cTco inch 10CD iD (D ▼ — ·· v- · σί T- ^ r CO r- -v CO o ^ 00 &lt; 〇tn -CO r- T— r— I 1681,1319 / 1162; S1340 inch CVJ CO o 'O) in tn BU T- Melting point (decomposition ϋ m.ptCC) 196-197 241-243 _I 157-159 175-176 145-147 183-186 183-184 224-226 * P4 Pi X JCQ * o h3c〇 ^ 〇- i X § ( CH3) 2CH- (CH3) 2CH-;. -1 (CH3) 2CH · (CH3) 2CH- _.. I (ch3) 2ch · (ch3) 2ch- 〇 Example No. in -r to t. Bu CO 7 CD; ^ o in ΙΟ 50 200403216 Table 1 2 {«) HOOo + HNNOSacc α: Η elementary analysis 1 i I C18H21N〇4S2.0.2H2O Calc. C: 56.43 H; 5.63 N: 3.66 8: 16.74 F. un.C: 56.74 H: 5,67 N: 3.86 S: 16.35 II \ 〇2 ^ Η | βΝ2〇482 # 〇.3Η2〇! Calc. C: 58.40 H: 4.34 N: 6.45 S: 14.85 Foun. C: 58.40 H: 4.44 N: 6.58 S: 14.57; C17Hi4CIN3〇6S-0.3H2 Calc. 0: 47.48 H: 3.44 Cl: 8.39 N: 9.65 S: 7.52 Foun.C: 47.57 H: 3.43 Cl: 8.26 N: 9.79 S: 7.47 1 IR (v cm-1) a®r) 1 1685,1349 1166 1691,1567 1390,1159 OJ inch O) CD l〇 *-Inch CVJ bu c〇τ— y — | 1746,1337 ί 1164. I 1649,1337 1165 ^ 1588,1308 1141 / 1744,1592 1323,1160 inch bu co N CO * »— h ^ CM l〇CO bu ^-r-τ- r— r- melting point (decomposition system m.pt.〇C) _-J Ί i 157-160 j II 111-112 -1 194-195 1197-199 108-110 187-190 239 -243 222-224 * Pi Pi 90 Oi 〇 £ ί Learn &lt; y〇r hoochQk (H3C) 2N-hT ^, i &gt; ί 0 ^ CH2 · &lt; Qkch2_ C ^ cHr (CH3) 2CH- or = X 'Z 〇DicH2- 8 / == ^ uz Q ^ £ ί Ο Γ = χ2 Q Example No. CO LO CO ΙΛ »Λ lO ΙΛ tO w inin 1 00 1Λ ιη

-51- 200403216 £) HOHNOOOH ^ osda: S〇§9 x〇2 ^? -〇-: 5¾ nSI? 2 ϊ SJ · 1¾ Ιμ stub δ -Λ * ϊ3 'ω 5ΐ Η CM ^ Λχ οα —j τ- ΙοΓ Μ CV 勹 古 η Inch · χ •• Producing 5 £ 45χ Τ3 τ— t— S. cd jy X ν— Ε Ν τ— &lt; 〇Sx II ^-5ε X &lt; η Γ; ϊΓ oi ^ .x ΪΪΜν ° i ν5 &quot; un ^ 3tn J * 〇j 4 Β was 5 £ X r ^ m 4 Urn · -T · fs · KJ * i _ S. 4 «'Ssl OJ r- 〇 爰 in- tt ^ η S £ 5? ΐ s &lt; 〇 ** 4 ice c \ j ， ① bu 00 oi s E sc \ is cvi reserve production £ νϋχ g-s Ik f O l〇O CVJ 5J2 B2 Art · CO II · Baiai 1 SS s if) ^ r- ss CD ^-f S ir- inch ** 卜 Si &lt; 9 * 1- Cvi4 go tn! 〇 ▼-▼-· ss ^ CO CO SS in t · * f: Si &lt; 0 COv ^ V— S £ 5 ss l〇T- ^ c3 CD 〇? S CO rr C〇ir- * cvT S ①T- &gt; r- r ^ · ss N · C〇V- T- 裟| e 11 麓 si € 0 5 T— I 5 &gt; ά Inch τη- 1 1 I 1 * cm «CO Ρί m X βί ό ό ό ό ό Φ ό Φ ό Φ ό Φ ο ό ο ό ο ό Ο χζΗ ο ο χΓ ο ± £ ο £ O £ / = j oz 〇έ ο ^ 〇iox / HQ LL Ci £ o 〇 / = 7) O-Z o m〇 铒 Z ο &lt; 〇 to ·, &lt; 〇 Γ〇 &lt; 〇 T to-ΙΛ &lt; 〇 &lt; 〇 Bu

-52 · 200403216 (B1) ΗΟΟΟΟΗίδέα: ΝΝΜβ (δ ppm) da-DMSO 2.72 (dd, J = 8.7, 13.6Hz. 1H), 2.94 (dd, J = 5.6, 13.6H: s, lH) 3.84 (ddd, J = 5.6, 8.7.Θ.7Η2,1 Η), 8.23 (ϋ, J =: 8.7H2, 1H) 2.88 (dd, J = 7.4, 15.2Hz, 1 H), 3.07 (dd, J = 6.2, 14.4Hz (1H), 3.83 (m, 1H), 8.08 (m, 1H), 10.80 (s, 1H), 12.70 (br, 1H) (d, J = 8.4Hz, 1H) 0.89 (d, J = 7.0Hzt3H}, 0.98 (dJ = 6.8 H2 &gt; 3H) f2.12 (m, 2H), 3.80 (dd, J =: 4.7 &quot;, 9.7Η2,1Η), 5.17 (^^ 9.6Η2 # 1Η) 2.78 -3.10 (m, 2H) 3.67 (s, 3H), 3.86 (m, 1H) 2.34 (s.3H), 2J5-3.08 (m, 2H), 3.86 (nUH &gt; · 8.19 (dfJ = 8.4H2,1H ) -—- 1 '丨 2.78-3.08 (m, 2H) 3.85 (m, 1 H) t8.18 (d, J = 8.6Hz, lH) 2.55 (st3H), 2.79-3.11 (m, 2H), 3.98 I ^ ^ 2400-3600br, 3345, 3213, 1735, 1700, 1346, 1163 j 3410.3276, 1724, 1582, 1488, 1331, 1152 (Nujol) _i 3412, 1724, 1582, 1488. 1332, 1152 co CO od CO (D 5t- oj in BU CVI r— y— · ^ Fco in 〇〇CO ^ 3273,1724,1582,148¾ 1331,1198,1153 cvj CO in uf co CM UD «— two, two r-bu 00 Oi CVJ -r-CO ^ 〇) O CO Inch C〇CO I 3415.1725,1582,1488, I 1329,1196,1174,1152 Inch 04 O UJ CO 1- CO CO CO r- C \ J 〇J inch Xibu CO * 5C · cn co CM l〇CO T- melting point (decomposed black m.pt: CC) 108-109 _I 82-87 foam V • 137-138 I l I 236-237 * P4 CO P4 ss CO X 〇-0〇- o * ° o ~ QrOr ： 6 〇 Qr &lt; y OQr 0-0- I or = X2 O o / = X2 o (ch3) 2ch O X / = j OZ O \ &quot; W .. or = X2 Q u. N £ x 〇8 / == oz o Example 丨 No. o «3 CM VO CO CD to to to &gt; D -53- 200403216 • (sHOOo ^ HI ^ OScoa: Yuan Zi Fen Qi I C24H22N2O7S2 Calc. 0: 56.02 H: 4.31 N: 5.44 S: 12.46 F〇un.C; 55.75 H; 4.40 N: 5.41 S: 12.21 \ 1 ί δ) IR (ν cm-1) (KBr) O CM σ &gt; χη ΙΟ CM v— r— coW OO l〇CO UQ T- * t— T— 1735,1583 1362,1171 I 1733,1583 1150 Melting point (Decomposition ^ m.pt.〇C) &gt; 240 I 1 * s 30 Oi Φ 〇Φ § Ο: 〇ώ-cH. • Μ δ 5 Q j COOC2H5 O * Lch2- Lion Case No. 00 CJ) 〇 Bu

-54- 200403216 6 Table (Qo HQHNOO ^ HNcv / osabla: S〇CO W Paintings are free of charge &lt; q 27 T xfU mQ Twenty-one fix ε® n τδ2 ςτ · buy $ «111 &lt; d cvi ^-Dagger 04 2 m inches? Τ &lt; ς co σ) »cvico S:-,-X 9 ^ r CO 2 CO · x ο σ &gt; X Let 45 · 3Sg d cvi co δ 1 s 04 &amp; CVJ τ- q CO 5f II ^-3 E ss d cv? L I | ff§ £ °? H: i〇 在 X 〇—) 二 二 σ l # | 〇 &gt; »/ &gt; &lt;. C \ [卜 'C \ i § K Ip §p * cvi E in! £ ^ &gt; § W 〇 一 s §s O CO Si2 I · O &lt; D ss C3 r- ci &lt; D ^ ί 2 ε Ο l〇W το s co CO T- &lt; 0 (D cJ3 〇CM CVJ ΤΟ C \ J t 1 2 μS I:-0 C5 SI2 8S N &lt; D CO r- 1 · * m 骟 Φ 〇 耀 δ O r— fg } &gt; 1 CO s 1 * P: Οί ot Φ inch £ o 妾 o! bu X o £ 0 1 ¢ 9? 〇 £ Ο £. ο 6 CM X o ό all a 0 ^ £ J Ο ό 士 Ο x / i 〇 ^ £ 1 ϋ 0 〇χ2Π 〇ti »—4 rr] • 'CO ΙΟ t t- tv --55- 200403216 7 1 Table (ql) HOHNOo / * \ HNolos &lt; 0l £ E Ή-ΝΜϋ ( (5 ppm> dc-DMSO 2.79 (ddiJ = 8.5l13.4Hzl1H), 2,89 (ddt J = 6.0, 13.4Hz, 1 H), 3.81 (ddtJ = 6.0 * a.5H2_1H) .6.55 (dJ = 15.5Hz, 1H) 2.78 (dd, J = 8.6,13.4Hzt 1H), 2.91 (ddTJ = 6.0, 13.4Hz, 1 H), 3.92 (ABq, J = 13.5 Hzf 1H) _3.90 (Π1 · 1Η) · 9 · 01 (5 · 1Η) · 10 · 78 (5 · ΊΗ) I s 25 3700-2400 (br), 3312, 1629, 1329, 1144 j 3700-2200 (br), 1670, 1318,1152! Rong (decomposed black m.pt〇C) | • I 138-139 69-70 1 * cti zo Oi 〇 ^ h2- i & &lt; 0hCHr Q ^ · 1 〇Δ -〇η2. Example 1 No.! * 1 0000 σσ &gt; • 56- 200403216 8 1 Table ω)) Η000 / *, ΗΝ2ο99α: &gt; H-NMR (6 ppm) dfi.DMSO N · '111 N —3. _ igs: BU &lt; 〇 &lt; 5 * 24 Kai d. 0.88 (t, J = 6.9Hz, 3H), 2.55-2,73 (m, 2H), 2.9 7 (dd, J = 8.4, 13.8Hzi1H) l3.24 (ddlJ = 4.8l13. 8Hz, t H). 4.35 (m · 1 H), 4.98 (m, 1H) (CDCb) ^ n * 3 51S8 〇1 · $ £ §4 £ s · ° ί 4 ch ^ -2. xxg inch ΙΟ ^ co ^ even Α 备 ο -α X "ι〇 工 NJiS 51 ^ &lt; 6 inches, fe 2i ^ £ ^ NS 1.55 2 ^ e · 思 · 〇_ &lt; 〇 CM »-i- 3.03 (dd, J = 6.5, 15.1 Hz JH), 3.15 | (dd, J = 4.7t14.1Hzl1H) i3.64 (t. J = 5.1Hz, 1H), 10.68 (s, 1H) £ xx Z?-CD 9x2 x ££ ^: 5λ σ &gt; »-S ^ &gt; 1 S £ 5 oi n hi M ^ -xx 5 h i &gt; co N o X q ii co to Fei Zhao x 〇S -.xx ca secondary production -j 产 σ &quot; co PH · 'inch · co 2! -ci § g for: q 2 1 £ β: S CD Ci co 1 ^' y &gt; 111 two X ' ο ο — l S) IR (v cm-1) (KBr) 1 CO n each 10f · ss 9 ^. §2 &lt; 〇 &quot; id S5 * C〇0 xf O CO S $ 2 * Κ §5 Is- CO CO 'f— 8¾ to 1 CO is L〇f— ΤΓ- ▼ — y— C3 Si2 CO &lt; 〇s N r— CvT So Good 〇7 §S Sit ccT R! T— co · &lt; 〇 §1 • Q b 8¾ N ”cp — §5 .S12 §5 s-g 2 r-Γ ^ S? Sa · 2 S Li 2 state e Si V ss 〇Λ m 1 1 1 CtS oi Pci. «oi 9» Φ so 1 N * o? o 1 η £ Ο ί * ο £ V w P δ 6 〇ό z ό I CM 5 0 〇0 υ ό ^ CJ o / = xz oar = TZ. O _P4 a: όέ * ο £ £ O xz o m6 »&quot; m BU ri •, co bu c〇N ¢ 0 0 Ν. Cn 57 57- 200403216 col) HOOo ^ H ^ osicc ί Yuan Zhe points 1 I C24HigN3〇5S * 1,3H2〇Calc. 0: 59.45 H: 4.49 N: 8.67 S: 6.61 Foun.C: 59.43 H: 4.45 N: 8.59 S: 6.58 I t 1 fi ) lR (i / cm-1) 1 (KBr) | &lt; 〇 inch O) wm r-; ·: · o inch h- CO »— r— 1576.1356 1139 1732,1342 1167 1745,1590 1316,1157 μ CD 00 in co inch o σ &gt; ο in cm melting point (decomposed tired m.pt.〇C) 153-155 —___ i &gt; 130 _ 128-130 I i 210 * 214 198-200 * P4 Pi VC a: 3 n -CgH ^-i 2 ^ 0 5 tt ft 6 Q-CHa- ^ £ 1 〇xzH Q / == xz Q Example No. 〇00 r— # 00 Cl CO co 00 呷 00 Luxury · -58 · 200403216 Table 2 Ο (£ χοχΝΟ0ς ^ ΗΝ &lt; \ 1οω € 6ια: cc

-59- 200403216 2 (el) KOOO ^ HNWOWOCC table -r ix β Q letter 4 t t ^: x S: ^ T ° 4. TJ r- x§? Two &lt; 〇, g ttSi σ &gt; co τ- ϊ ^ -3 5SS '工 X -3 (ΰ ^ grf〇 &gt; _ (〇 一 V in α &gt; ^ §.μ · § 52 d CSJ 05 X cf (〇 ^ ϊ ιο ^ £ Μΐ r Ν * ^ χϊ Ιί4 ^^. • Ό 卜 C0 二 CNj r- Ιιg CO II §st _ §§ li g ^ · ρ ω ί〇2 8S Sit CO cjido §S2 O ^ ioti2 1 _ · o ^ S mi 1 'm έ jj τ ι S S C CVi Λ 8 * ¢ 5 CA w oa Cxi Φ 6 0 ζ ό ζ 1 Φ zx 〇 = &lt; 2X ό u £ ο ό Ο〇 ό _ i * 1 o ό @ 〇ΙΟ 00, Ώ! &Quot; Bu, 00 • 60- 200403216 2 E hooo ^ hnc ^ s.bcc Table. Ύ Element analysis 1-CO CO T- ci co ΊΤ- * r- co (o in N Vol. J cq cq Zhao to (〇 * t 2 2: O) production 〇C0 &lt; 0 kxif O-SS S〇〇 (0 〇〇〇〇 cvi cvi T- * T- CO CO cvj in ^; 5 Ν3ωΙ CO 〇〇co 〇 x ^ 〇qd (3 £ I CgiH ^ gBrNgOsSg ^ SCFgCOOH Calc. 0: 44.30 H: 3.30 Br: 13.40 N: 4.70 S: 10.7 &amp; IF〇un.C: 44.62 H: 3.52 Br: 13.07 N: 4.64 S: 10.85 i) IR (vcm.l) (KBr) 1719,1390 1229 T- CO cd in rr T- t- inch ' rC CO CVi N C3 ♦ — t— 1724,1325 1168 1735,1598 1327,1185 Melting point (decomposed black nx.pt.CC) 103-106 I 96-99 I 110-112! 98-101 * cd 05 a # 30 I Qs; ii-〇- Φ zx &lt; n &lt; D Φ m C &amp; ch2 · (ch3) 2ch · '· (CH3) 2CH- Example No. 03 00 a 00 ow ^ 4 a 0 0 -61- 200403216 »Example 9 2 (Method B) 1st process:

2nd process HCI Ξ Η 2N 8 COOMe XV-2

XVI1M

MeO— ^ ~ y

'J-SCVN

-N COOH b H

Ia-2-1 ⑩ In the first process, D-valinic acid methyl ester hydrochloride (also 2) 7 5 5 11 ^ (4.5111111〇1) was dissolved in 12 ml of dichloromethane, and N- Methylmorpholine (3 X 4.5 mmol) and 5-bromothiophene-2-sulfonyl chloride 1.24 g (1.05 X 4.5 mmol). After stirring at room temperature for 15 hours, it was sequentially washed with 2N hydrochloric acid, 5% sodium bicarbonate water and water, dried over sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3) Crystallize with n-hexane to obtain melting point 109-1 10. (: Target substance (χνΐΙ-1) 1.32 g (82% yield). Lu elemental analysis C1QH14BrN04S2 Calculate 値 · C; 33.71 Η; 3.96 Br; 22.43 Ν; 3.93 S; 18.00 Experiment 値: C; 33.75 Η; 3.89 Br; 22.43 Ν; 3.96 S; 17.86 [a jo-34.5 soil 0.7 (c = 1.012 CHCb 25X :) IR (CHCl · ,, v max coffee)> 1737.1356, 1164, 1138 NMH (CDC13,5 ppm): 0.89 (d, J = 6.8Hz, 3H), 1.00 (d, J = 6.8Hz, 3H), 2.00 (π, ΙΗ), 3.60 (s, 3H), 3,83 (dd , J = 5.2,10.0Hzf 1H), 5.20 (d, J = 10.0Hz, 1H), 7.04 (d, J = 4.lHz, lH), 7.32 (d, J = 4.lHz, lH). -62 -200403216 In the second process, 40 mg (1.1 2 mmol) of compound (XVII-1) was dissolved in 5 ml of dimethylformamide, 222 mg (1.5 × 1.22 mmol) of 4-methoxyphenylacetylene and sodium iodide (I ) 21mg (0.1xl.12mm0l), fully degassed under argon atmosphere. Add bis (diphenylphosphine) gasification (II) 39mg (0.055X 1.12mmol) and triethylamine 0.47ml (3 × 1) · 12mmol), and then fully degassed under argon atmosphere. After stirring and heating at 50 ° C under argon atmosphere for one night, it was diluted with ethyl acetate, followed by 1N salt acid, 5% sodium bicarbonate water and water. Washed, dried over sodium nitrate, concentrated under reduced pressure, and separated on a silica gel column layer (N-hexane / ethyl acetate = 2/1), ethyl acetate / n-hexane was recrystallized from to afford the desired product melting point of 131~132 ° C (XVIII-1) 392111 eup, yield 86%.

Analysis 値 C19H21N05S2 · 0.2H2O Calculation 値: C; 55.51 C; 5.25 Ν; 3.41 S; 15.60 Experiment 値: C; 55.80 Η; 5.19 Ν; 3.38 S; 15.36 IR (KBr, v max 011 ^ ) 3268,2203,1736,1604,1524,1348,1164 NMR (CDC13, δ ppm): 0.90 ((1, J = 6.6Hz, 3H), 1.00 (d, J = 7.0Hzt3H), 2.00 (m, lH ) t 3.60 (s, 3H), 3.84 (sf3H), 3.86 (dd, J = 5.0,10.2Hz, 1H), 5.2l (d, J = 10.2 Hz, lH), 6.90 (d, J = 9.0Hz, 2H), 7.44 (dlJ = 9.0Hz, 2H) &gt; 7.12 (d1J = 4.0Hz, 1H), 7.44 (dfJ = 4.0Hz, 1H) In the third process, 407 mg (lmmol) of the compound (XVII-1) was dissolved IN NaOH 5.1 ml was added to 8 ml of tetrahydrofuran and 8 ml of methanol, and after heating and stirring at 60 ° C for 6 hours, the organic solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and acidified with citric-63-200403216 citric acid water. Extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give compound (Ia-2-l) 3 7 3 mg (yield 100%)

Melting point · 1 4 7 ~ 1 4 8 ° C

IR (KBr, ^ max cm · 1): 1710, 1604, 1351, 12 16 Elemental analysis C18H19N05S2 · 0.2H2O Calculated 値: C; 54.45 Η; 4.92 Ν; 3.53 S; 16.15 Experiment 値: C; 54.39 H; 4.93N; 3.79S; 15.96 φ Example 9 3 ~ 1 5 6 The compound of Table 2 3 ~ 30 was synthesized as in Example 9 2. -64- 200403216 200403216 (Bl) HOOO + HNCIOSC61DC icr Elemental Analysis I ^ 26 ^ 22 ^ 2 ^ 5 ^ Calc. 0: 65.81 H: 4.67 N: 5.90 S: 6.76 Foun.C: 65.34 H: 4.90 N: 5.56 S : 6.40 II f II 〇2βΗ2〇Ν2〇63 * 0, 4Η2〇Calc. C: 63.00 H: 4.23 N: 5.65 S: 6.47 Foun.C: 62.99 H: 4.32 N: 5.82 S: 6.76 C25H21 N3〇4Se0 »8H2 〇Ca (c. 0: 63.36 H: 4.81 N: 8.87 5: 5.77 Foun.C: 63.45 H: 4.92 N: 8.77 S.6.57 丨 1 &amp;) IR (v cm-1)! (KBr) 1 1590, 1316 1137 1747,1323 1134 1724,1325 1135 1739,1336 1163) &gt; -r- CO \ 〇t-1— T- οσί, 1- CvJ N CQ T-- CO c〇t— c〇 ¢ 0 in co CVJ N- i-— 1706,1606 1350,1164 i CO CO CO BU CO -r- nc \ j BU C5 Fusion S &amp; (decomposition Si m.ptOC) 165-170 223-226 I _I 216-218 111-114 | 178-180 105-108 &gt; 250 176-177 liters Pi Ρί P P4 Di 〇 ~ c = c-〇- h3co- ^ Q-cechQ- HOH0 ^ CEC ^ 〇h h3coco-^) ~ cec-^)- ^ Qn: -zJOr ° 2n * -〇kcech〇 ^ hooc ^ Q_cecHQ ^ Φ 〇Φ ί {Z CrV ,, C0-ch2- I Όώ-c- CAch2- cicH, CiicH, o / = xz Q 士 ϋ ί =工 ζ Q Example: No. CO 05 叩 σι »n σ &gt; ID BU cn CO i cn a ο ο- 66- 200403216 yd :. 2021) hoooohncds.bo: Table cc Elemental analysis C26H22N2〇4S-0.2H2〇Calc. 0: 67.57 H: 4.89 N: 6.06 S: 6.94 F〇un.C: 67.66 H: 4.77 N: 6 , 09 S: 6.71 1 l 1 IC ^ gH ^ 0N2〇6SBO.lH2〇Calc. C: 56.46 H: 4.54 N: 6.93 3: 7.93 Foun.C: 56.30 H: 4.37 N: 7.14S: 7.85 II 1- 6 ) IR (v cm-1) (KBi ·) 1736J618 1398,1168 1735,1654 1399,1164 T- CO CO inch &lt; D Yr— 〇i CvT CO N BU CO Y— T- · 1600,1558 1 1336, 1171. I 1795,1718 1331,1166 1719,1595 • 1344,1167 -r- CO COinch ¢ 0 &lt; »-r— r— ocT c \ TC \ JN CO y ~ 1728,1332 1172 Melting point (decomposition Black m.pt.〇C) 227-229 230-233 234-236 &gt; 200 decomp. 146-149 .231-232 166-169 163-165 * CtJ &gt; «Pi Pi Pi Oi hc = c ^^^ c = chQ &gt;-02N h3c〇hQ) ^ cec ^^-h2n-hQ ^ cec ^ Q- 〇ώ-c; CA〇h2- (CH3) 2CH- (ch3) 2ch · (CH3) 2CH- (CH3) 2CH寊 例 No. 〇p—1 CM 〇1—4 CO of—t inch omooi — * Bu o 00 o • ♦ 67-

200403216 5 2 Table {e〇χοοο / νχϊ ^ ώΈ Elemental analysis 1 I C21H23N05S.1.3H20 Calc. 0: 59.36 H: 6.07 N: 3.30 S: 7.55 Foun.C: 59.36 HI6.06 N: 3.50 S: 7.44 I f I! C23HiqFN〇4S * 0.3H2〇! Calc. 0: 64.41 H: 4.37 F: 4.43 N: 3: 27 S: 7.48 Foun.C: 64.37 H: 4.38 R4.96 N: 3.31 S: 7.24 I 5) IR (v cm-1) (KBr) 1720,1656 | 1319,1165 in oo co to &lt; 0 y- T— Ύ— rftO CM CD co f— 1711,1683 1600,1328 1159 | o r- CO CO CD- rr- cvT〇) O OJ K CO T- * 4 in r— inaS. ro ^ rt $ 2 1,727,1604! 1335,1182 CO N- &lt; D 05 &lt; D T-: cm σ &gt; bu co -1728, 1332 1172 Melting point (decomposition ^ ni.pt.CC) 187-189! 111-114 161-162 157-159 133-136 J 183-185 166-168 163-165 * &gt;pc; (¾ ci 90 cc I H3C〇H0KC = C-^-h3C〇-〇-c = chQ- h3c〇H0kc = c- ^ Q ^ I 丨 H3C ^ O ^ cec〇- h〇-〇-c = c-〇 &quot; (CH3) 2CH- (CH3) 2〇H- __________ j (ΟΗ3) 3〇- I — o & &lt; Q ^ ch2 · [Jkch2 · I (CH3) 2CH- i Example No. 0¾ oo — CO -r in, _ __4 200403216 2l-HOOO ^ HN ^ OS.9cn table; 索 yuan cable analysis 1 II 1 1 1 I ^ 18 ^ 19N〇sS2 * .2H2〇Calc. 0: 54.45 H: 4.92 N: 3.53 S: 16.15 Foun.C: 54.39 H: 4.93 N: 3.79 S: 15.96 1 &) IR (v cm-1) (KBr) to in in CO CO T- T- · ΊΟ 0 &gt; CJ bu &lt; 〇r— Ύ— in QD co m &lt; D T- ▼ — ^-· C \ J &lt; 0 h- CO r— 1585,1318 1153 r CO ·· -CNJ l〇 \ 〇1-r— r— 10 * 0 o arm «3 CO inch CO CM» »O CO. CO r? T— &quot; T ~! 1721,1620 ί / 1339,1163 1729, 1675 1340,1168 1710,1604 1351,1216 Melting point (decomposed black rn.pt.CC) 187-189 111-114 167-169 I 1 103-106 180-182 147-148 * Pi Pi &gt; ¢ 5 X ^ Qr ^ Qr 〇τ ^ &gt; ~ ^: 々H3C〇-^)-c = c- ^ V- H3c-^-c = c-^-h3co-^^^ cec- ^ V · a: (CH3) 2CH- _ £ 1 〇F = X2: Q 〇ώ-〇Η2. CM δ / r = r · XZ .Q a / = 工 2 〇 (ch3) 2ch · Example No. Bu PH CO 1 19 O CO « -4 r *-&lt; CM 〇] Cl CO 03 ^ -4 C) • · -69- 200403216 2 (el) HOOoOHN ^ OS.Sir Table T element analysis C ^ gH ^ gN〇4S2 * 0.2H2〇Calc 0: 56.73 H: 5.13 N: 3.68 S: 16.83 Foun.C: 57.03 H: 5.30 N: 3.89 S: 16.56 I C22H ^ gN〇5S2 * 〇.2H2〇Calc. C: 59.36 H; 4.39 N: 3.15 5 : 14.41 F〇un.C: 59.43 H: 4.61 N: 3.25 S: H.02 I 4 C21H16FNO4S2 Calc. 0: 58.73 H: 3.75 R4.42 N: 3.26 S: 14.93 Foun.C: 58.66 H: 3.93 F: 4.52 N: 3.33 S: 14.41 1 1 1 S ) lR (i / cm-l) (KBr) _1 1712, 1350! 1163 I 1710, 1499 1356, 1165 1695, 1334 1184 1710, 1329 1180 1734, 1699 1324, 110¾ 1 1 1 Melting point (decomposed black m.pt . (C)! 157-158 l 154-156 149-150 161-164 II 155-158 i 1 1 1 Pi Pi Pi Oh Pi Di ¢ 5 CcJ ao Csi H3co ^ Q ^ c = cJ ^-h3ch〇)- c San 1 OCHa G ^ CiC-Q ~ 'och3 H3CO h3co-^-c = c- ^ ~ HaCO' \ N〇2 (CH3) 2CH-. (ch3) 2ch- ...... J _ £ l 〇0 ·,丨 0 ^ cH2- i &lt; 〇HCHr &lt; Q ^ ch2- &lt; 〇KCHr Example No. Cl r-f Bu 00 C ^ l-CO 03 〇-70- 200403216 2 (Bl) Hooa ^ HNWOS, Bo: Table T element division 1 1 1 I f 1 1 1 1 1 IR (v cm ^ l) (KBr &gt; 1 1 1 1 1 1 1 \ i Melting point (decomposition S m.pt, CC) 1 1 1 1 1 1 1 1 * Pi Pi &gt; (¾ 90 Oi (^ c = c ^ Q- N〇2 ch3 (CH2) 5-cec-^^ — h3c〇hQ-c = chQ- H3co- ^ c.c4 ^-hoh ^)-c = o ^^-0d 0 ~ cHr o 6; 〇-CHa- &lt; 〇 ^ CHr ^ £ J o ό &lt; Q ^ CH2 · o ό 0 ^ CH2- Example No. o CO 1—4 -r ¢ 0 * — » in CO • —4 CO •• —4 CO r—4 00 i c〇 CJi CO r— &lt; c • -71-200403216

2 (01) Ηοοα ^ Η ^ ο ^ α: Yuan 粜 fenqi I 1 1 1 f 1 1 1 1 1 S) IR (v cm-1) (KBr) 1 1! 1 tf 1-1 and 1 I Point (decomposition ιί m.ptCC) 1 \ iil 1 II * Pi ¢ 5 Pi ¢ 5 oc cd _i F3CH ^ HCHC-^ — O ^ Q-cic ^-丨 · rQr 沈 \ ί hooch ^^ ~ c = c- ^^ — MeOOC-^^-C Three C ^ cHr CJ ό Qr% ^ £ 1 o 6. (J ό 1 &lt; Q ^ ch2- Example No. | -rr * H CO w ^ 4 — ID π KD 1 rr 9-4 bu n * p ^ 4 00 T -72- 200403216 3 (eo hooooh ^ os.bo :. 1 1 1 1 1 1 l 1 1 1 5) IR (v cm-1) 1 (KBr) ! 1 1 1 1 I 1 I Melting point (decomposed black m.pt.〇C)!! 1 1 1 1 i 1 1 * Pi Pi Qi 05 act a H2NOC-^^-CiC-^^ — Me2N ~ ^^ -C = C-^ — 1 Me02SH ^ y-CEC · ^^ — nc ^ C3 ~ cec &quot; w ^ s ^ — G ^ CHr (^ -ch2-. _1 &lt; Q ^ ch2- C ^ -ch2 · o ό ^ CJ 〇ό 0 ^ CH2- 0 ~ CHr Example No. σ &gt; rr 9 ^ 4 o in rt in to CO to ^ -4 ΙΛ rH i〇ΙΛ • H &lt; D m • · -73- 200403216 Implementation Example 1 5 7, 1 5 8

ρ II Lso N eight c00MeAl ^ l ^ s Η XVIII-2 X)

MeO— / ~ Λ ~ ^ JLsjLs〇2 ’eight COOH pj2

Ia-2-66 · Ia-2-67 〇 1st process (r2 = ch3) 150 mg (0.33 mmol) of the compound (X V111 -2) synthesized in Example 9 6 was dissolved in 2 ml of dimethylformamide, After adding 227 mg (5X 0.33 mmol) of potassium carbonate and methyl indium (5X 0.33 mmol), the mixture was stirred overnight at room temperature, and then poured into water. It was extracted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 373 mg of N-methyl compound as an oil (yield 91%). Analyze 値 C 2 4 Η 2 3 Ν Ο 5 S 2 Calculate C · C; 61.39 H; 4.94 N; 2.98 S; 13.66 Experiment 値: C; 6 1.22 H; 5.18 N; 2.93 S; 13.27 The product 140 mg was dissolved in methanol 2 m Bujia 1 NN a 0 H 0.6ml 'After stirring at room temperature overnight, it was acidified with 2N-HC1. Extracted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 105 mg of compound (Ia-2-66) (R = Me) with a melting point of 185 to 186 ° C (yield 77%)

Analyze 値 C 2 3 H 2 i Ν Ο 5 S 200403216 Calculate 値: C; 60.64 Η; 4.65 N; 3.07 S; 14.08 Experiment 値: C; 60.56 H; 4.84 N; 3.01 S; 13.94 IR (KBr, v max cm * 1) 3600-2300br, 3426, 2203t 1710, 1604, 1503, 1344, 1151 NMR (de-DMSO, δ ppm): 2.88 (s, 3H) f2.93 (dd, J = 12.0, 10.2Hzt 1H ), 3.19 (dd, J = 14.2,5,6Hz, lH), 3.81 (s, 3H), 4.74 (dd, J = 5.4,10.2Hz, 1H), 6.997.04 (m, 2H), 7.20-7.35 (m, 7H) t7.52-7.56 (m &gt; 2H), 6.90 (d, J = 9.0Hz, 2H) i7.44 (d, J = 9.0Hz, 2H), 7.12 (d, J = 4.0Hz, 1H) &gt; 7,44 (d, J = 4.0 Hz, 1H) In the same manner as in Example 157, R2 = CH2Ph compound (Ia-2-67) was synthesized. IR (KBr, v max 0111 ^): 2200, 1722, 1340, 1151 φ NMR (de-DMSO, δ ppm): 2.94 (dd, J = 7.6, 13.8Ηζ, 1Η), 3.19 (dd, J = 7.2, 14 · 4Ηζ, 1Η &gt;, 3.83 (s, 3H), 4.29 (d, J = 16.2Hz, lH &gt;, 4.62 (d, J = 16.2Hz, lH) (Special Example 1 5 9 (C method ) 2nd process

Br —jLs〇2i / ^ c〇〇Me -tm Me〇-^^ ~ JLsjLs〇2_㈡ 八 COQMe XIX-l

XVIM 1st process

Me〇-H ^^^ sjLs〇2-N ^ COQH

Ia-3-1 1st process: 500 mg (1.4 mmol) of the compound (XVII-2) obtained in Example 96 was dissolved in 12 ml of dry tetrahydrofuran, and 387 mg (2 × 1.4 mmol) of powdered potassium carbonate and 319 g of 4-methoxyphenylboronic acid were added. (1.5 × 1.4 mmol), 81 mg (0.05 × 1.4 mmol) of triphenylphosphine IE, and stirred at 75 ° C. under argon atmosphere for 48 hours. Diluted with ethyl acetate, washed sequentially with 1N-hydrochloric acid, 5% sodium bicarbonate water and water, dried over sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (n-75-200403216 hexane / ethyl acetate). Ester = 3/1), crystallized from n-hexane to obtain 447 mg (yield 83%) of the target compound (XIX-1) with a melting point of 122-123 ° C. Elemental analysis c17H2] N05s2 Calculated 値: C; 5 3.2 5 Η; 5.52 Ν; 3.65 S; 16.72 Experimental 値: C; 53.26 Η; 5.50 N; 3.69 S; 16.63 [α] &gt; 21.7 TU 0.6 (c = 1.000 DMSO 25 * C) IR (KBr, u max € 03 ^) 1735,1605,1505,1350,1167,1136 NMR (CDCh, &lt; 5 ρριη): 〇90 ((M =: 7.00Η; 3Η &gt; · 1 · 00 (&lt; 1 · &lt; I = 6 · 6Ηζ, 3Η)) ^ JL0 (m, · lH), 3.54 (s, 3H), 3.85 ( s, 3H) _3′7 (dd, J = 5Al〇-2H2, lH), 5.20 (d, J = 10, 2H2, lH), 6.94 (d, J = 9.0H2, 2H), 7-52 (d , J = 9.0H: 2,2H) .7.11 (d, J = 4.0H2, m), 7.49 (d, J = 4.0Hz, lH) In the second process, the compound (XIX-1) 3 9 0mg (l. 01 mmol) dissolved in a mixture of 8ml of tetrahydrofuran and 8ml of methanol, force [] IN NaOH 5.1ml, stir and heat at 60 ° C 6

After hours, the organic solvent was distilled off under reduced pressure, diluted with ethyl acetate, acidified with citric acid, extracted with ethyl acetate and washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 373 mg (yield 100 %) Compound (la-3-

Melting point: 1 7 4 ~ 1 7 6 〇C IR (KBr, v max cm-1) · 1735, 1503, 1343, 116 3 Example 1 6 0 ~ 1 7 5 Example 1 5 9 Synthesis Table 3 1 ~ 3 2 compounds. • 76- 200403216

3 M X000 / VX2W0W.® ^ Table.cc Element analysis 1 I 1 〇22 ^ 20 ^ 2 ^ 4 ^ 3 * ^ · ^^ 2 ^ Calc. 0: 55.07 Η: 4.37 N: 5.S4 S: 20.05 Foun.C: 55.35 Η: 4Α3 Ν: 6.04 S: 19.65 II C15H16FN〇4S2 * .1H2〇I Calc. 0: 50.15 H: 4.55 F: 5.29 N: 3.90 S: 17.85 F〇un.C: 49.99 H: 4.58 R5.22 N: 4.05 S: 17.77 C16H19NO4S3 Calc. C: 49.85 H: 4.97 N: 3.63 S: 24.95 Foun.C: 49.70 H: 5.00 N: 3.93 S: 24.96 1 IR (v cm-1) (KBr) 1 1667,1337 1180 ί 1670,1339 1194 CO ιο Οϊ CO ΙΟ ▼-S: · CM NO τ— τ— 1735,1341 1159 ^ C〇C0 Ο (Ο ιη _ »— τ— uieo * ο ττ C3 1713,1353 / 1163 inch CO O &lt; D U7 Tr— τ- c \ ic \ T o in CO 1747,1324 1159. Melting point fenjie m.pt.〇C) 93-96 ί 157-159 _ί 168-171 226-230 174-176 165 * 167 146-147 157-159 * • 尨 Ρ4 Pi &gt; ai erf SO Οί η3〇ο'ηΟ _ ^^ $ IL · h3csh ^ &gt; ~ ^ V • h3co-H ^ 4 ^ tf $ li. A £ Ο-/ = Χ2 Ο CAch2- I Ο χ / &quot; ο ο = χζ Ο (CH3) 2CH. (Ch3) 2ch · 1 (CH3) 2CH- 1 (CH3) 2CH -Example ϊ No. 1 j Ο iD ψ1 · 4 οι »— (C0 CO« — * to i〇 VC ID

• 77- 200403216 2 (3: Table (el) H〇oo + HN &lt; VJos06la: Elemental element C20H19NO5S2 Calc. C: 57.54 H: 4.59 N: 3.35 S: 15.36 Foun.C: 57.62 H: 4.72 N: 3.52 S; 15.27 ^ 20 ^ 19 ^^ 4 ^ 2 Cala 0: 59.83 H: 4.77 N: 3.49 S: 15.97 F〇un.C: 59.77 H: 4.86 N: 3.61 3: 15.86 C19H16FNO4S2 Calc. C: 56.28 Η: 3.9Θ F: 4.09 N: 3.45 S: 15.82 Foun.C: 56.33 H: 4.09 F: 4.65 N: 3.65 S; 15.84 C2〇Ht9N〇4S3-0.2H2 Calc. C: 54.95 H: 4.47 N: 3.20 S: 22.00 Foun.C: 55.05 H: 4.52 N: 3.34 S: 22.04 II i 1 \ fi) IR (v cnvl) | am 1735,1698 1374,1163 1713,1609 1378,1194 _i 1721,1654 1365,1148 1750,1730 1428,1325 1155 1 I 1 1 Melting point (decomposed l xn.pt, CC) 161-165 166-167 174-175 203-205 1 1 I • I * αί P5 Pi 9C oc h3c〇-〇- ^ X IL H3〇S-〇-^-I 0 lT «^ £ 1 0 Q-CHa- &lt; Q ^ ch2- 0 ^ CH2- ^^-ch2- Example No. 〇〇to CD to 0 卜 # -1 卜— BU • —4 CO BU—— &lt; BUIL-1 ΙΛ .¾ s. · 78 200403216 Example 176 (Method D) HC1Η〆'COO «Bu 02N-^-S02-N ^ C00 * Bu 2nd process XX-1 3rd process XV-3 H2N-^^ S02-N / ^ C00tBu XX I-1 〇 〇 〇〇〇, ιι — · Μ · ^ XXII-1

COOH

Ia-4-1 In the first process, 10 g (4 7.6 8 mmol) of D-valine tert-butyl hydrochloride (χ V-3) was dissolved in 100 ml of dichloromethane, and the solution was cooled under ice. Add 5.7ml (3X47.68mm) of N-methylmorpholine and 14.1g (1.2X47.88mmol) of 4-nitrobenzenesulfonyl chloride sequentially, and stir at room temperature for 5 hours, then sequentially with 2N hydrochloric acid, Washed with 5% sodium bicarbonate water and water ', dried over sodium sulfate, concentrated under reduced pressure, and recrystallized from dichloromethane / n-hexane to obtain a melting point of 89-90 ° C (XX-1) 1 3,3 g (77.8% yield). Elemental analysis c15h22n2 06 s Calculation 値 · C; 50.27 H; 6.19 N; 7.82 S; 8.95 Experiment 値: C; 50.04 H; 6.10 N; 7.89 S; 8.84 200403216 [a] d-2.9 ± 0.8 (c = 0.512 DMSO 23X :) IR (KBr, v max cm · l) 3430br, 3301,1722,1698,1525,1362,1348,1181, 1174,1159 The second process will be 13.29 g (37.08 mmol) of compound (X-1) Dissolve in 200ml of methanol, add 1g of 10% Pd-C, and reduce with hydrogen catalyst at room temperature. After 2 hours, the catalyst was filtered off, concentrated under reduced pressure, and recrystallized from acetone / n-hexane to obtain 11.5 g of an amine (XIX · 1) with a melting point of 1 64 to 166 ° C (yield 94.4%). Elemental analysis c15h24n2o4s Calculate 値: C; 54.86 Η; 7.37 Ν; 8.53 S; 9.76 Experimental 値: C; 54.84 Η; 7.33 Ν; 8.63 S; 9.50 [α] 0 + 10.3 · 1.0 (c = (K515 DMSO 23t :) IR (KBr, v max 0111-1) 3461,3375,1716,1638,1598,1344,1313 NMR (d ^ DMSO, δ ppm): 0.80 (d, J = 6.8Hz , 3H), 0.82 (d, J = 6, 6Hz, 3H), 1.23 (s, 9H), 1.83 (m, m), 3.30 (m, lH), 5.86 (s, 2H), 6.56 (d, J = 8.8Hz, 2H), 7.36 (d, J = 8.6Hz, 2H), 7.47 (d, J = 9.6Hz, 1H) In the third process, the compound (XXI-1) 3 2 8 mg (l mmol) was dissolved in two 10 ml of methyl chloride was added sequentially under ice-cooling 0.33 ml (3 × 1 mmol) of N-methylmorpholine and 280 mg (1.5 × 1 mmol) of 4-methylthiomethyl chloride. After stirring at room temperature for 1 night, diethyl ether was added. The crystals were collected, washed with ice water and ether, and recrystallized from acetone / ether to obtain 43 3 mg (yield 90.5%) of the target compound (XXII_1) at a melting point of 2 3 5 to 2 38 ° C. Elemental analysis c23h3Qn2o5s2 Calculate 値: C; 57.72 H; 6.32 N; 5.85 s; 13.40 • 80-200403216 Experiment 値: C; 57.63 Η; 6.28 Ν; 5.86 S; 13.20 [a] D + 5.7 soil 0.9 (c = 0.512 DMSO 25t :) IR (KBr, i / max cm-1) 3366,3284,1713,1667,1592,1514,1498t 1341,13 17 NMR (d6-DMSO, δ ppm): 0.82 (d, J = 6.6Hzi3H), 0.84 (d, J = 6.8Hz, 3H), 1.22 (s, 9H) ,: L91 (m, lH), 2.55 (s, 3H), 3, 32 (s, 3H), 3.44 ((id, J = 6.2, 8.6Hz.lH) 7.40 (d, J = 8.6Hz, 2H) t7.73 (d, J = 8.6Hz, 2H) J7.90-8 , 01 (m &gt; 5H), 10.48 (stlH) Λ In the fourth process, 405 mg (0.85 mmol) of compound (XXII-1) was dissolved in 3 ml of dichloromethane, and 3.3 ml of trifluoroacetic acid (5 0 X 0.8 5 mmol) was added. Stir at room temperature for 2 hours. After concentration under reduced pressure, it was washed with ether to obtain a melting point of 2 3 1-2 3 4 ° C (I a-4-1) 340 mg (yield 94.7%) °

Melting point: 2 3 1 ~ 2 3 4 ° C IR (KBr, 2; max cm · 1): 1748, 1 65 5, 1 5 9 2, 1 3 2 3, 1161. Elemental analysis c19h22n2o5s2.o.icf3cooh Calculate 値: C; 53.14 H; 5.13 Ν; 6.46 S; 14.78 Experimental 値: C; 53.48 H; 5.31 N; 6.57 S; 15.06 Example 1 7 7 ~ 2 0 8 Example 1 6 The compounds of Table 3 3 to 36 were synthesized. -81200403216

M HO〇OOHNC \ IOS.®0: Yuan Yuan analysis (^ 25 ^ 23 ^ 3〇65 * 0.99 ^ 2〇Calc. 0: 58.91 H: 4.90 N: 8.24 S: 6.29 Foun.C: 58.97 H : 5.07 N; 7.95 S: 6.10 l 〇24H2〇N4〇7S * 1.1 HgO Calc. 0: 54.56 H: 4.24 N: 10.60 S: 6.07 F〇un »C: 54.51 H: 4.32 N; 10.83 S; 6.15 C26H26N4O5S. 0.9H2O Calc. 0: 59.73 H: 5.36 N: 10J2 S: 6.13 Foun.C: 59.58 H: 5.23 NH0.8S S: 6.47 C25H23N3〇5S * 0.9H2〇Calc. 0: 60.82 H: 5.06 N: 8.51 S: 6.49 Foun.C: 60.83 H: 5.19 N: 8.66 S: 6.66 〇24 H2〇BrN3〇5S * 0.6H2〇Calc. 0: 52.11 H: 3.86 Br.14.44 N: 7.60 S: 5.80 Foun.C: 52.13 H: 4.04 Br: 14.57 N: 7.43 S: 5.70 ^ 25 ^ 23N3〇sS2 * .7H2〇Calc. 0: 57.50 H: 4.71 N: 8.05 S: 12.28 Foun.C; 57.63 H: 4.79 N: 8.00 S: 12.08 1 i) IR (v cm-1) (KBr) 1732,1641 1341,1163 ΙΛ 卜 in n &lt; D Ty— t— CO * CO cvj cvj and C5 t— T— CO 〇 &gt; CO inch &lt; D r -CNJ tD N · CO 1719,1629 1340,1156 1732,1653: 1399,1199 1731,1656 1591,1327 1160 CO CO CO T- (O CO &lt; ○ inch cm 〇) m BU Yan 1728,1653 1593 , 1323 1159 melting point (decomposition Si rn.pt. (t)) 215-217 I 233-234:] _ 216-218 211-213 -------! 236-238 240-244 215-218 244: 249 * Pi P4 Pi Pi Pi a ¢ 5 90 a: Φ to X oo ό h3c〇H〇 ^ c ^^-I Φ fX OO Φ | Φ T worker · oo Φ s * (H3C) 2n ^^ c-nhQ ^ Φ fi oo Φ o CO X slave ^ Qr%-^ Qr H3CS ^^ gNH〇 ^ Cxi ο / = X2 .〇i Q £ o 12: Q CS-〇h2- Οά-CH, ΟΔ-ch, s Example No. 卜卜 ^^ 4 CO N • —4 Oi 卜 F— »o co X 00 Γ0 XTX

82- 200403216 4 3 Table (el) HOOo + HNCVJosQba: Elemental analysis C24H20FN3OsS.0.6H2O Calc. C: 58,55 H: 4.34 R3.86 N: 8.54 3: 6.51 F〇un.C: 58.67 H: 4.51 F: 3.77 N: 8.42 S: 6.47 ^ 23 ^ 22 ^ 2〇6 ^ Calc. C: 60.78 H: 4.88 N: 6.16 S: 7.05 Fun. G: 60.50 H: 4.99 N: 6.14 S: 7.31 C22H19N3O7S Calc, C : 56.29 H: 4.08 N: 8.95 S: 6.83 Foun.C: 56.01 H: 4.09 N: 8.93 S: 6.75 C22H2〇N2〇5S * 0.5CF3COOH Calc. 0: 57,37 H: 4.29 N: 5.82 S: 6.66 Foun .C: 57.53 HAAS N: 5.75 S: 7.11 C22H19BrN2OsS-CF3COOH Calc. 0: 46.69 H: 3.27 Beta 2.94 N: 4.54 S: 5.19 Foun.C: 46.79 H: 3.41 Br: 12.86 N: 4.57 S; 5.37 C23H22N2O5S! Calc. 0: 63.00 H: 5.06 N: 6.39 3: 7.31 Foun.C: 62.70 H: 5.13 N: 6.36 S: 7.36 C23H22N2〇5S2.〇.8CF3COOH Cafe. 0: 52.59 H: 4.09 N: 4.99 S: 11.42 Foun .C: 52.77 H: 4.24 N: 5.12 S: 11.58 C22H19FN2O5S Calc. 0: 59.72 H; 4.33 F: 4.29 N: 6.33 S: 7.25 I Foun.C: 59.59 H: 4.42 F: 4.30 N: 6.37 S: 7.24 1 IR (v crn-l) (KBr) 1730,1651 1603,1333 1161 T- CJ l0 &lt; \ J &lt; D CO r— r— CO ▼-T— CM C7) (O ·· T— 1 — R — T— 1719,1672 1593,1327 1159 co in in c \ j &lt; d &lt; n T— τ ~~ · aS oj σ) inch σ) in Nin r- * r— 1743,1670 1591,1335 1167 (_ £ _ 1752,1726 1656,1591 / 1324,1160 &lt; 〇CO 2 inch O) CD • Buin · »-y— t— inch in cm CD CO t— r ^ co 0 〇〇〇 &gt; & lt 〇 卜 l〇T— T— V— * Melting point (decomposition m.pt. (* C) 170-175 237-239 235-239 114-115 242-243 242-244 II 232-235 1 218-220 | * Pi P5 CSJ 70 a Φ fX oo h3c〇H〇-cn-Qk 〒 工 OO Φ Φ · OO Φ m h3cs- ^ c ^ h〇 ^ Φ zr 00 Φ li- _ £ lor = xz Q &lt; Q ^ ch2- h &lt; 〇 &gt; -CHr O &lt; Q ^ ch2- IQ ^ ch2- Example No. ΙΛ OO &lt; D • CO Γ ΟΟ CO. 00 1 8.9 t 1 — «· — &lt; O ' · Γ1 83- 200403216 3 {e〇Η〇〇〇〇 ^ ΗΝ ^ · 9α: Yuan Zhifenxin c21h18cin3o5s Calc. C: 54.84 H: 3.94 Cl: 7.71 N: 9.14 S: 6.97 Foun. C: 54.39 H: 4.06 Cl: 7.42 N: 8.98 S: 6.99 C22H20CIN3O5S * 0 · 1 cf3cooh Calc. 0: 55.15 H: 4.19 0: 7.33 N: 8.69 S: 6.63 Foun.C: 55.25 H: 4.28 01: 7.10 N: 8.80 S: 6.80 C24H24N2O5S -0.5hl2O Calc. 0: 62 * 46 H: 5.46 N: 6 .07 S: 6.95 F〇un.C: 62.42 H: 5.54 N: 6.26 S.6.97 C ·) 9H22N2〇5S * 0.2H2〇Calc. 0: 57.91 H: 5.73 N: 7.11 S: 8.14 Foun.C: 57.94 H: 5.69 N: 7.03 S: 8.14 C19H22N2〇5S2 * .1 CF3COOH Calc. C.-53.14 H; 5.13 N; 6.46 S: 14.78 Foun.C: 53.48 H: 5.31 N: 6.57 S: 15.06 CieHi9FN2O5S * 0.1CF3COOH Cafe. 0: 53.86 H: 4.74 R6.09 N: 6.90 S: 7.90 Foun.C: 53.82 H: 4.85 F; 5.60 N; 6.93 S; 7.78 〇18 latch 2 (^ 2〇58 * 0.1 HgO Calc. C: 57.16 H: 5.38 N: 7.41 S: 8.48 F〇un.C: 57.01 H: 5.46 N: 7.57 S: 8.57 ^ 19 ^ 22N2〇6Sb〇.2H2〇Calc. 0: 55.65 H: 5.51 N: 6.83S: 7.82 F〇un.G: 55.63 H: 5.48 N: 7.03 S: 7.75 1 IR (v cm-1) (KBr) 1724,1673 1592,1326 1156 CNJ CVJ CO CO CO o in cvTo OJ O) &lt; D bl 10 rr— t— r— o inch ID Oi CD CO t— t— CO O cn &lt; o L L〇r · t— r— CO CO in &lt; vi «3 CO C} 〇Jy- inch σ &gt; (〇 卜ΙΟ Τ- t〇CQ in cvj ω co co *-cJ »-yT &lt; J) &lt; £ &gt; in 1- t— r— &lt; 0 0 CM 05 &lt; D r ^. In T- Ύ- * T ~ T— &lt; i &gt; 〇 □ c \ T inch CD CVJ KCDCO 1— t— T— bu &lt; D CD CO t- &gt; C 〇C7 &gt; cm 〇 &gt;in; N IO -r- τ ~ · -r— r ~-Inch · in v-co co co * r- * in cn σι in CO UOCM r— ir- melting point (decomposition s rn.pt.CC) 201-203 206-208 254-256 ί 227-229 II 231-234 235-236 226-227 220-221 · * Pi ίϋ 30 Φ fX oo &lt; &gt; · o Φ fX £ Φ fX OO Φ fOOOO φ £ H3cs * O ~ g-I Φ fX OO Φ P OO o 6 (ch3) 2ch- 丨 (ch3) 2ch- (CH3) 2CH- (CH3) 2CH- (CH3) 2CH (CH3) 2CH. Example No. CO T cn 0 ^ im 〇 &gt; • X) αι »—1 N σ &gt;! RH 00 cr.» CTi 9 &quot; ♦ 0 ·· -84- 200403216

3 《el) HOOO ^ HNCDs ^ a: Yuan Yuan analysis C ^ gHigN3〇7S * 0.4H2〇'Calc. C: 50.44 H: 4.66 N: 9.80S: 7.48 Fun. C: 50.40 H: 4.55 N: 9.90 S; 7.44 Cl8H19BrN2O5S * 0.2Ethylether Calc. 0: 48.03 H: 4.50 巳 r: 17,00 N: 5.96 S: 6.82 F〇un.G: 48.04 H: 4.61 Br: 16.83 N: 5.96 S: 6.86 C2〇H24N2〇 6Se0.4H2〇Calc. 0: 56.17 H: 5.84 N: 6.55 S: 7.50 F〇un.C: 56.21 H: 6.02 N: 6.50 S: 7.33 〇2i H2〇N4〇5S * 0.25CF3COOH Calc. C : 55.06 H: 4.35 N: 11.95 S: 6.84 Four ».C: 54.80 H: 4.90 N: 12.16 S: 7.10 C21H19N3O5S Calc. 0: 59.28 H: 4.50 N: 9.88 S: 7.54 F〇un.C: 58.84 H: 4.56 N: 9.71 S: 7.36 ^ 20 ^ 19 ^ 3〇6δ Calc. 0: 55.94 H: 4.46 N: 9.78 S: 7.47 Foun.C: 55.50 H: 4.47 N: 9.74 S: 7.31 I 1 1. Ϊ ) ΊΗ (ν cni-l) (KBr) OO CO inch &lt; 0 C3 T— t— &lt; 0 ^ (0 OJ O) CD BU l ** T— &gt; r-- CO 00 C〇T- tDCO CO CV〇5 oj C7 &gt; m BU I T- rr produced T— 03 cn in lO T- σίω ιο · »-&lt; DC〇 ^ t— r cn 〇CD C〇T— T— COO CJ CVJO) QD Bu lO T- 'T— ir1719,1672 1594,1339 1165 x in σ &gt; 00 production &lt; D CO ▼ — T— c5V inch CQ O) to l〇 ^! 1732,1679 1592,1312 ί 1155 1 Melting point (decomposition m.pt.CC) 240-242 229-230 214-216 236-237 I 272-275 214-215 217-220 1 * Di Pi X Oi fX oo Φ-^ Qr HsCO-Qc-nhQ- 〒 工 OO o £ Φ fX OO ό Φ 〒 工 OO io 1 ZX Φ CD Φ 〒: E OO Φ ζά (CH3) 2CH- (CH3) 2CH-: (CH3) 3〇- [^ ~ ch2 · IG ^ CH2- II 〇 Example 1 No .; ir-4 0 01 c \ o Cl Γ0 oo CM ΙΛ 〇Cl to 0 i 〇) Bu CJ OO 0 CM

85- 200403216 Example 209 (Method E) HC1

Η2Ν ^ ΟΟΟιΒυ i.1. Process &gt; Factory-introduced C〇〇 〖Bu Bu XV-3 — XX1IM Process OHC-Eight COQtBu Third Process XXIV -1-"N = C-In 000 Oil 11"

η ~ ^ Ν = Ν

MeS— ^ /

Ia-5-1

SCVH C00H In the first process, D-valinic acid tert-butyl ester hydrochloride (XV-3) 2 0.94 g (9 9.8 mm. 1) · Dissolved in dichloromethane 2 0 0 m, and then added N under ice cooling. Methylmorpholine 22mi (2X99.8 mmol) and p-styrene sulfonyl chloride 20.27 g (99 · 8 mmol), stirred at room temperature for 15 hours, followed by 2N-hydrochloric acid, 5% sodium bicarbonate water and water Washed, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / n-hexane / chloroform = 1/3/1), and washed with n-hexane to obtain a melting point of 118-120 ° C. (XXXII-1) 28.93 g (85% yield). -86- 200403216 IR (KBr, v max 012 ^) 3419,3283,1716,1348,1168 NMR (CDCl3, δ ppm): 0.85 (d, J = 6.9Hz, 3H), 1.00 (d, J = 6.6Hz , 3H), 1.21 (s · 9H), 2.04 (m, lH), 3.62 (dd, J = 9.8, 4.5Hz, lH), 5.09 (d, J = 9.8HZ &gt; lH), 5,41 (dd · J = 0.5, 10.9Hz, lH), 5.84 (dd, J = 0.5, 17.6Hz, lH), 6.72 (dd, J = 10.9, 17.6Hz, l_H), 7.49 (d, J = 8.4Hzf2H), 7.79 (d, J = 8.4Hz, 2H) In the second process, 5.09 g (15 mmol) of the compound (XXII-1) was dissolved in 300 ml of dichloromethane, and ozone was added at -78 ° C for 15 minutes, and then added. 22 ml of methyl sulfur (20 X 1 5 mm ο 1) was prepared at room temperature in 80 minutes, and then concentrated under reduced pressure to obtain 6.03 g of aldehyde (XXIV-1). Lu IR (CHCh, v max ¢ 11 ^) 3322,1710,1351,1170 NMR (CDC13, 6 ppm): 0.85 (d, J = 6.9Hz, 3H) F1.00 (d, J = 6.9Hz, 3H) , 1.22 (s, 9H), 2.07 (m, 1H), 3.69 (dd, J = 4.5, 9.9Hz &gt; 1H), 8.01 (s, 4H) 110.08 (s, 1H) The third process converts the compound (XXIV-1) 6.02 g (15 mmol) was dissolved in a mixture of 60 ml of ethanol and 15 ml of tetrahydrofuran, and 2.72 g (1.05 X 1 5 mmol) of sulfenylhydrazine was added. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure, and recrystallized from ethyl acetate by silica gel column chromatography (chloroform / ethyl acetate) to obtain a melting point of the target compound (χχν_1) of 1 63-1 64 ° C. 4 · 44 g, yield 60% from the second process. Calculated by elemental analysis C22H29N3〇6S2 値: c; 53.32 Η; 5.90 N; 8.48 S; 12.94 experimental 値 ·· C; 53.15 Η; 5.87 Ν ; 8 · 32 S; 12.82 [α] D-11.6 ± 1.0 (c = 0.509 DMSO 23.5 ° C) 200403216 IR (KBr, v max cmd) 3430r3274,1711,1364,1343,1172 NMR (CDCl3, δ ppm ): 0.84 (d, 4 = 6.91 ^, 311), 0.99 ((1, J = 6.6Hz, 3H), 1.19 (s, 9H), 2-00 (m, lH), 3.63 (dd, J = 4.5 , 9.9Hz, lH), 5-16 (d, J = 9.9Hz, lH), 7.50 ·

7.68 (m, 5H) f7.73 (s &lt; lH) (7.78-7.84 (ml2H) l7.96-8.02 (mi2H), 8.16 (hrs.lHY 4th process will be 4-methylhydrothioaniline 0.14ml (l .llXlmmol) dissolved in 50% ethanol aqueous solution, add 0.3 ml of concentrated hydrochloric acid, and stir at internal temperature 0 ~ 5 ° C. Add sodium nitrite 7 8.4 mg (1.14 X 1 mm ο 1) water 1 The m 1 solution was stirred at the same temperature for 15 minutes. In addition, 496 mg (1 mmol) of the compound (XXV-1) was dissolved in 5 ml of dry pyridine, and the aforementioned reaction solution was added with 8 minutes while stirring, at -15 ° C to room temperature. After stirring for 4 hours, it was poured into water. It was extracted with ethyl acetate and washed with 2N hydrochloric acid, 5% sodium bicarbonate water and water in that order, dried over sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography (chloroform / ethyl acetate). Ester = 1/9) to obtain 3 74 mg (74% yield) of the target compound (XXVI-1). Elemental analysis C23H29N5 04 S2 · 0 · 3Η20 Calculated 値: C; 54.27 Η; 5.86 Ν; 13.76 S; 12.60 Experiment C · C; 54.25 H; 5.77 Ν; 13.87 S; 12.52 IR (KBr, v max cnr ”3422.3310,1705,1345,1171, NME (d6.DMSO, δ ppm): 0.83 (d , J = 6.9Hzt3H), 0.86 (d &gt; J = 7.2Hz, 3H). 1.19 (s, 9H), 2.00 (m, lH), 2.59 (s, 3H), 3.54 (dd, J = 6.3,9.6Hz , lH), 7.56 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.7Hz, 2H), 18.33 (d, J = 9.6Hz, 2H), 8.34 (dfJ = 8-7Hz, 2H) In the fifth process, compound (XXVI-1) 3 5 3mg It was dissolved in a mixture of 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid, and after stirring at room temperature for 3 hours, it was concentrated under reduced pressure and washed with ether to obtain 30.8 mg of compound (Ia-5-l) (yield 98%). ). _ -88-200403216

Melting point: 1 9 4 ~ 1 9 5 ° C IR (KBr? V max cm'1) · 1 7 2 0, 1 3 43, 1 1 6 6, Elemental analysis c19h21n5 04 s2 · 1 · 1Η20 Calculate 値: C 48.83 Η; 5.00 Ν; 14.99 S; 13.72 Experiment 値: C; 49.13 Η; 5.25 Ν; 14.55 S; 13.34 Example 2 1 0 ~ 2 5 1 Example 2 0 9 Synthesis Table 3 7 ~ 4 3 compounds.

200403216 Table tcc HOHNOoOHNWOra: &amp; 〇 &lt; 〇g This QS ά ^ 1 1 σ ιι ^ ΙΙξϋ- mu Hilt 4 ^ 15 1 co n £ 0 工 5 * xin * ㈤s㉔ CJ -3 XC〇〇) I, g 1 «* w I? 〇〇Si 52 §si〇 $ 2 2¾ it 1 s V» i T— 90 &amp; £ z · 2 0 -.- 2 ό a K, δ · 工 广 ο ^ £ 1 o ό m ^ 〇W2 ο ···

-90- 200403216

3 (el) ΗΟΟΟΟΗ ^ οπΒα: JH-NMR ((5 ppm) da-DMSO! 2.75 (dd1 J = 9.3,13.7Hz, 1H), 2.99 (dd, J = 5.3,13.7Hz, 1H) 5.3,9.3Hz , 1H), 8.53 (d, J = 9.3Hz · 1H) l Ϊ) IR (v cm * l) 〇CBr) 1 2400-3700br, 3422, 3337l 1733, 1698, 1347, 1170 mmmi rn.pt.CC) 1 215-216 * ct; ao d af = xz 6 &lt; 〇 »CHr Example No. O CVJ rH 9 1 CM

-91- 200403216 3CO0 ΗΟΟοΟΗΝο'ίΛέα: Table T Elemental Analysis C25H22N6〇4S * 〇.5 Ethylether Cate. C: 60.10 H: 5.04 N: 15.57 S: 5.94 Foun.C: S0.41 H: 4.69 ΝΠ5.52 S: 5.57 〇24 latch, gFNgO ^ S.OMElhylether Calc .C: 57.35 H: 4.32 F: 3.54 N: 15.67 S: 5.98 Foun.C: 56.74 H: 4.37 R3.47 N.M5.17 S: 568 ^ 19 ^ 21 N5O4S Calc. 0: 54.93 H: 5.0.9 N: 16.86 S: 7.72 F.un. C: 54.75 H: 5.14 N: 16.81 3: 7.55 C18H19N5O4S Calc. 0: 53.38 H: 4.83 N: 17.29 S: 7.92 Foun. C: 53.38 H: 4.80 N: 17.05 S: 7.67 I • 〇28 ^ 23 ^ 5〇45 * 0.6 ^ {2〇Calc. C; 62.70 H: 4.55 N: 13.06 S: 5.98 Foun. C: 62.61 H: 4.50 N: 13.29 S: 5.87 C26H21N5O4S.0.2H2O Calc. 0: 62.07 H: 4.29 N: 13.92 5: 6.37 Foun.C: 61.93 H: 4.30 N: 14.01 S: 6.43 〇25Η2〇Ν6〇5 $ · Η2〇Calc. 0: 56.17 H: 4.15 N: 15.72 S: 6.00 Foun.C: 56.20 H: 4.18 N: 15.68 S: 6.10 1 &amp;) IR (v cm-1) (KBr) CD CO CO CO BU T- 1728, 1338 1166 1720,1595 1338,1170 1696,1594 1349,1173 1727,1337 1163 10 〇0) to inch T- T— T— in co &quot; co co CO 1721,1418 1344,1163 1727,17 03 1459,1332 1165 Melting point (decomposed black m.pt. (* C) 199-202 224-225 202-204 221-222 I 145-148 203-205 225-227 111-114 * 30 tv: $ 6 π Z Z-2 ό I. 6 $ b 6 a f1 o £ H uz Q (CH3) 2CHCH2- {CH3) 2CH- CHO 〇-Lch2- Quality Example No. · — &lt; Cl CO Cl T • —1 Cl i / 3 w ^ 4 CsJ bu 00 4 O) cr. • -92- 200403216 Table 4 〇 cc

(njo HOODOHN20SCOCC element analysis C25H22N6O5S Calc. 0: 57.91 H: 4.28 N: 16.21 S: 6.18 Foun.C: 57.77H: 4.29 N: 16.01 3: 6.37 C19H21N504S Calc. 0: 54.93 H: 5.09 N: 16.86 8 : 7.72 Foun.C; 54.71 H: 5.09 N; 16.70 3: 7.56 〇2〇Η23Ν5〇§3.0.4 · 2ΗCalc. C: 53.06 Η: 5 · 30 N: 15.47 S: 7.08 F〇un.C: 53J3 H: 5.13 N: 15.12 S: 7.14! F C20H23N5O5S-0.4H2O Calc. C: 53.06 H; 5.30 N: 15.47 S: 7.08 Foun.C: 53.13 H: 5.13 N: 15.12 S: 7.14 Cl8H18BrNs〇4S * 0.8H2 〇Calc. 0: 43.70 H: 3.99 Br: 16.15 N: 14.16 S: 6.48 Foun.C: 43.93 H: 3.85 Br: 15.92 N: 13.87 3: 6.47 I 1 1 ^ IR (v cm-1) 〇CBr) I 1749,1719 • 1331,11.65 _I 1730,1693 1349,1173 CO 0 CJ) t〇Tr ™ ▼ — oV OJ 〇h- C3 T— T ™ 1718,1601 1385,1162 1719,130¾ 1162 9 1696,1348 1171 1698 , 1344 1168 CO CO CO CD BU— * Is · »T— 10 CJ N CO Melting point (decomposition i! Ltt.pt. (* C) 195-196 • 205-207; 1 _1 204-207 190 decomp. I ί 195-197 j 227-228 204-207 203-205 * P3 Pi P4 Pi w h3c〇-〇-^^-h3coh ^ -n.n &lt; ^^ Ηο-Ο-ζ ^ Ο- h3c〇-〇 - ^ &gt; 0-0 &amp; Lch2-! CH3CH2 (Chb) CHCH3CH2 (CK3) CH * (CH3) 2CH- (CH3) 2CH- (CH3) 2〇H- (CH3) 3c-OCicH, Example NO. 〇C) Cl «—4 CJ ίΊ OJ CO OJ" 4 tfi Cl CM UD C ^ J CM 93- 200403216 1 ± 4 Table

ml) hooo ^ hnnosoo: a 2-element cable analysis I C23H18F3N5O4S Calc. C: 53.38 H: 3.51 R11.01 N: 13.53 S: 6.20 Foun.C: 53,11 H: 3.55 F: 10.B9 N: 13.66 S: 6.31 Calc. C: 52.67 H: 3.78 N: 16.73 S: 6.39 Foun.C: 52.73 H: 3.92 N: 16,53 S: 6.55 C22H18FN5〇4S * 0.2H2 Calc. C: 56.09 H: 3.94 R4.03 N : 14.87 8: 6.81 Foun.C: 56.10 H: 4.09 F: 4.12 N: 14.84 S: 7.08 C22H18CiN5O4S * 0.6H2O Calc. C: 53.41 H: 3.91 Cl: 7.17 N: 14.16 S: 6.48 F〇un.C: 53.33 H: 3.90 Cl: 7.22 N: 14.19 S: 6.68 ^ 23 ^ 21 N5〇4S * 1.2H2〇Calc. C: 56.94 H: 4.86 N: 14.44 3: 6.61 Foun.C: 56.88 H: 4.49 N: 14.31 S: 6.72 ^ 23 ^ 21 · 7Η2〇Calc. C: 54.15 H: 4.82 N: 13.73 S: 6.29 F〇un.C: 54.05 H: 4.35 N: 13.60 S: 6.77 18 ^ 6〇4 ^ · 〇.8Η2〇Calc . C: 56.50 H: 4.04 N: 17 / .9 S: 6.56 Foun.C: 56.52 Η: 4 · 16 N: 17.C0 S: 6.52 [i) IR (v cm-l) (KBr) in CVJ n Inch to Nr-r- y— 1738,1707 1328,1169 1730,1597 1345,1161 1730,1509 1236,1165 CO inch O) CO ΤΓ r- T- r— 0 co &quot; CO inch BU · CO N CO 〇O ) h- f ^ · «Ο CQ vy- &quot; v cJ σΓιη r &gt; o inch h- in o r- r- N- CO &lt; Ji CD &lt; 0 π Qiao CO inch Bu CO 1731,1605 1336,1160 Melting point (decomposition system m.ptCC) 197-199 197-198 190-191 205-207! _ 204-206 226-227 214 -216 190-192 * Pi 04 Pi .L Φ 〇ιΓ 02nhQ ^ n &quot; n3hQ- i F 普 ^ 〇 &quot; H3C〇-〇-^ / ^ ct: Qkch2- 〇 &gt; ~ CH2 · I € ^ -ch2- ο ό 0 ~ CH2- G ^ ch2- o 6 Example No. 〇〇CMCl 0 CI 0 ro CO CM cn 01 CO CO Cl 2 34 in Γ0 C ^ J -94- 200403216 Table 4 2 筲 一) ΗΟΟο ^ ΗΝ &lt; \ ιοω &lt; ησ: cc elemental element C26H27N504S Calc. C: 61.77 H: 5.3BN: 13.85 8: 6.34 Foun.C: 61.59 H: 5.45 N: 13.89 S: 6.27 C28H29N5O4S 0.3.20Calc. 0: 62.62 H: 5.56 N: 13.04 S: 5.97 Foun. C: 62.46 H: 5.52 N: 13,43 S; 6.28 1 I C24H | 9BrN5〇4S * 1.7H2O Calc. C: 48.20 H: 3.78 Br: 13.36 N: 14.05 S: 5.36 Foun.C: 48.27 H: 3.75 Br: 13.16 N: 14.11 S: 5.38 Calc. C: 58.49 Η: 4.56 Ν: 16.37 S: 6.25 F〇un.C: 58.52 Η: 4.69 Ν: 16.71 S: 5.90 Ci9H2iN5〇4S * 0.8H2O Calc. C: 53.09 H: 5; 30 N: 16.29 S: 7.46 F.un.C: 53.20 H: 5.14 N: 16.06 S; 7.70 CiaHt8FN504S * 0.2H2.Calc C: 51.11 H: 4.38 F: 4.49 N: 16.55 S: 7.5S Foun.C: 50.90 H: 4.37 F: 4.89 N: 16.28 S: 7.46 Including Chi: Ji Kun g 1738,1328 1314,1149 I Cvl CO Ί- 卜 ΙΟ t- K- CO CVJ S CO T— r— cocn 0 10 l〇r- ▼ — rCcvT CO inch to 04 [1713,1514; 1341,1159 ί CO T- CVJ, &lt; 2 inch * ' 〇 · 〇 &gt; Inch &lt; 35 ΙΟ n 呀 T-. 1718,1685 1334,1170 1716,1346 1165 (CM CO CO &lt; £ 3l〇0¾ inch r-in bu bu r "ί— melting point (Decomposition si m, pt.CC) 224-226 225-227 182-184 226-228 205-207! 199-201 206-207 208-209 · * P5 &gt; 30 oc ϊίζ ω g Φ § ί Ι, · ζ B · 2 Φ CD .ί $ Γ- 二 2 Φ 2 * 2: Φ LL 0 &quot; called I ............... ............. _ 一 | ό ^ TJ Ο r = χζ ο 丨 tflCH2 · I (CH3) 2CH- ί (CH3) 2CH- S. 〇 «Z &lt; Ώ CO 卜CO 〇〇n CVJ Ο) CO CVJ ο -τ -τ / c ^ j * T 0] n -r 7 &gt; 1

-95- 200403216 4 M XOOO / VX5W.SC Table Element Analysis 1 C ^ gH2tN5〇4S2 * 1.1 HgO Cala C: 48.83 H: 5.00 N: 14.99 S: 13.72 Foun.C: 49.13 H: 5.25 N: 14.55 S; 13.34 C23H21 Ν5〇々2 · 〇.2Η2〇Calc. C: 55.34 H: 4.32 N: 14.03 S: 12.85 Foun.C: 55.37 H: 4.35 ΝΠ4.00 S: 12.86 C25H22N6O4S2 · 1.1H2O Calc. C: 54.16 H: 4.40 N: 15.16 S: 11.57 Foun.C: 54.20 H: 4.66 N: 15.09 S: 11.62! Ct8Ht6N6〇4S-0.4H2 Calc. C: 51.52 H: 4.04 N: 20.03 S; 7.64 1 Foun.C: 51.34 H : 3.96 N: 19.76 S: 8.02 I 1 1 1 W IR (v cm-1) (KBr) 1696,1348 1171 CO 5 T— cS to CM CO TT— t— 1753,1497 1325,1165 ㈡ &lt; DC〇CO 100 r- 〇 &gt; N, Bu t t- r- τ- 0 n co to TT rt- r- CO N σ &gt; cm &lt; 0 co I 1 1 Melting point (decomposition ϋ nx.pt · (C) 223-225 194-195 _I 222-224 213-216 i &gt; 220 ί I 1 • 1 * P4 Pi Pi 1¾ ¢ 5 »Di $ 〇h3cs ^ X〇- H3〇s ^ = ^-! H3 〇s-〇-n ^ N = N / = \ οΗο-Ο-ζ ^ (CH3) 2CH- (CH3) 2CH- &lt; C ^ cHr o / = X2 Q ο Worker 2 Ο Q »ch2 · Q ~ ch2 ^ ca 〇0 Example No. in • r rj ’JD T BU -r 00 acryl σ &gt; CV3 0 to CNJ« -4 ΙΛ tvj

-96- 200403216 Example 2 5 2 Example 265 157 The compounds of Tables 44 to 45 were synthesized.

-97- 200403216 Table 44

α〇ώ 0.96 (dJ = 6.6H2,3H) 1.01 (d, 6.aHz.3H) 2.87 (s.3H) 4.17 (dJ = 10.4Hz, 1H) 0.71 (dJ = 6.6Hz, 3H) 0.88 (d. 6.4Hz, 3H) 2.88 (s, 3H) 3.48 (d, J = 10.8Hz, 1H) 0,55 (dJ = 6.8Hz, 3H) 0.82 (d, a6Hzt3H) 3.74 (s.3H) 0.91 (dfJ = 5.6 Hz.6H) 1.52-1.69 ^, 4 ^ 3.84 (dJ = 10.4Hz, 1H) 0.95 (dJ = 6.6Hz, 3H) 0.97 (d.6.8H2.3H) 2.89 (s.3H) 4.20 (0 .J = 10.6Hz, 1H) 0.92: 2.J = 6.6Hz, 3H) 0.97 ·· 3,6.6Ηζ, 3Η) 2.84iSt3H) 4.73ilJ = 7.4Hz.1H) 2.78 (ϋ = 13.8 · 7 · 2Ηζ · 1Η } 3.14 (da. = 14.8,7.4Hz, 1H) 4.43 (d, J ^: 6.4HztlH) 4.6a (dtJ =: 6.4Hz, 1H) 0 · 96 (〇υ = 6.4 · 4Η2:,: 3Η) 0.97 (d. ^ 6.4Hz, 3H) 2.52 (s.2H), 2.93 (st3H) IR (v cra-1) (KBr) 1715,1583 1340,1151 3323,1678 1328,1150 I inch σ &gt; CO inch CD T -r— T- inch · 〇 · ^ CM CO C〇C3 -r- 3700-2200br 1681,1319 1212 3300-2400br 1711,1336 1185 3300-2400br 1719,1340 1153 3640_2400br 1736,1717 1694,1346 1162 3284br, 1745 1714,1323 1131 Melting point (decomposition point) * · m-pt. (* C) 1 110-111 _i 148-150 I 206-207 132-132.5 1 141-144 * (si, Pi Ο Μ Οί -C00H- CONHOH -CONHOH -C00H -COOH -COOH -COOH -COOH σ &gt; Oi 3? 〇I? O &lt; 〇HCHr t • (ch2) 4nh2 〇-ch3 -ch3 90 α QrOr 1 QrO ·. 2 6 $ 22 ό H3CS-Q-i &gt; (CH3) 2CH- (CH3) 2CH- _ _. __ \ (ch3) 2ch- I (CH3) 2〇H- (CH3) 2CH- (CH3) 2CHCHr · (CH3) 2CH- Example No. 03 m CO tn or 1 \ no \ tn m \ n C \) X? IO cr &gt; »n -98- 200403216 Table 45

-99- 200403216 Example 2 6 7 The compound of Table 4 6 was synthesized as in Example 9 2.

100- 200403216 6 4 Table II) 8 ^ G: Ή-NMK (&lt; 5 ppm) d ^ .DMSO 2.62 (dd, J = 8.4l13.5H2i1H) l2.80 (ddl J = 6.0l13.5Hz, 1H) l3.82 (dddlJ = 6.0, 8,4,8 ^ 2,1 H), 8.38 (d, J = 8.7HzJH) 2.73 (ddlJ = 59.3,13.6HzJH), 2.96 (dd, J = 5.4,13.5Hz, 1H), 3.92 (dt, J? 5.4, 9.3Hz, 1H), 8.42 (d, J = 9.3Hzf1 H) 1 丨 IR (vcm-l) (KBr) 3700-2400brt3267, 2217,1671,1321,1161 2200 -3700brt3430, 3292,1728,1324,1162 Melting point (decomposition point 1 _i 156-158 176-178 * 〇 one CONHOH -COOH «0 QO- Qr ^ y Example 1 No. 1 N • Ώ Ol 200403216 below Experimental examples of the compounds of the present invention are shown, in which the test compounds correspond to those used in the table. Experimental Example (1) Isolation and purification of MMP-9 (92 kDa, gelatinase B) Refer to the following documents to purify type IV collagenase (MMP -9).

Scott M. Wilhelm et al5 J. Biol. Chem., 264, 17213-17221,

(1 9 8 9) SV4 0-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages; Yasunori Okada et al. J. Biol. Chem. 5 267, 2 1 7 1 2-2 1 7 1 9, (1 992) Matrix Metalloproteinase 9 (92-kDa Gelatinase / TypelV Collagenase) from HT 1 0 8 0 Human

Fibrosarcoma Cells; Robin V. Ward et al, Biochem. J.5 (1 99 1) 278, 1 7 9-1 8 7 The purification of tissue inhibitor of metalloproteinase-2 from its 7 2 k D a progelatinase complex. MMP- 9 is to take human fibroblastoma ATCCHT1080 as 12-fourteen? 11 () 1 * 11 hex-1-1-3 acetate (D? 8) was stimulated and secreted in the culture medium. Gelatin-zymogram method (Hidekazu Tanakaetal., (1993) Biochem. Biophys. Res. Commun "1 9 0 7 3 2-740, molecular colonization and expression of 105-kDa gelatinase cDNA in mice) The production of MMP-9 was confirmed. The culture supernatant of this HT1 080 strain was concentrated, and gelatin Sephalose 4B with concanavalin A (concanavalin

102- 200403216 A) Refined by Sephalose and Sephacryl S-200. The purified prO-MMP-9 (92 kDa, collagenase B) showed a single active band in the collagen-zyme method. Activated with trypsin twice to obtain active MMP-9. (2) Analytical method for type IV collagenase inhibitors The collagenase is made of the aforementioned MMP-9, and the matrix and measurement kit are made of Yagai's type IV collagenase activity measurement kit. The analysis method is according to the method of Yagai. The analysis of the inhibitor is based on the analysis of 1 compound (the inhibitor) as follows. (A) Matrix (type IV collagenase), enzyme (MMP-9), inhibitor, (B) Matrix (type IV collagenase), inhibitor, (C) Matrix (type IV collagenase), enzyme (MMP- 9), (D) Matrix (type IV collagenase). The fluorescence intensity was measured according to the analysis method of Yagai Co., and the obstruction (%) was determined by the following formula. Obstruction (%) = {1- (A-B) / (C-D)} X 100 IC5Q indicates that the concentration is 50%. The results are shown in Tables 47 to 54. 200403216 Table 47 Example No. Compound No. I C50 (/ zM) Compound No. I Cs〇 (uU) 1 la-1-1 0.2 4 lb-1-1 0. 0 3 0 2 la-1-2 2 6 lb * l-2 0. 04 3 la-1-3 0.18 lb-1-3 0.005 4 la-1-4 2.2 5 5 la-1-5 0 · 8 1 lb-1-5 0.041 6 la · 1-6 0.6 8 lb-1-6 0.034 7 lb-1-7 0.028 8 la · 1-8 .2, 0 lb-1-8 2.0 9 lb «X-9 * 0. 4 1 10 lb-MO 2 1 11 lb-Ml 1. 7 12 lb-1-12 0 * 0 8 .5 13 lb-1-13 0. 3 8 14 la-1-14 3. 7 lb-1-14 0. 11 15 lb -1-15 0.027 1 6 la-M6 0.520 lb · 1-16 0. 0 10 8 17 la-1-17 0.205 lb-1-17 0 · 0203 18 la-1-18 0.500 lb-1-18 0. 0 2 8 2 2 0 lb-1-20 0.134 2 1 la small 21 4.6 5 lb-1-21 0. 0 0 4 1 2 3 lb-1-23 0.073 2 4 lb-1-24 0. 2 2 6 lb-1-26 1. 3 2 7 lb-1-27 3. 0 3 0 la-1-30 1.16 lb'1-30 0.213 3 1 lb-1-31 0. 0 12 9

-104- 200403216

Table 4 8 Example No. Compound No. IC§9 (/ λM) Compound No. I C50 (uM) 3 3 la-1-33 0. 2 4 lb-1-33 0. 0 0 5 3 5 la · 1-35 2. 6 lb-1-35 0. 0 2 16 3 8 la · 1-38 0. 0 18 4 0 la · 1-40 0. 0 7 6 4 1 la-1-41 0. 3 1.2 4 2 'la · 1-42 0, 0 12 3 4 3 la · 1-43 0. 6 2 5 44 la-1-44 1.910 4 5 la-1-45 0. 0 4 0' 4 6 la-1 -46 1. 12 4 7 la-1-47 0. 3 8 9 · 4 8 la-1-48 1 · 15, 4 9 la-1-49 0. 2 4 9 5 0 la-1-50 0. 5 5 3 5 1 la-1-51 0, 110 5 2 la-1-52 0. 3 &gt; 2 9 5 3 la-1-53 1. 8 5 4 la-1-54 0. 0 7 5 5 5 la-1-55 0. 0 3 9 8 6 0 la-1-60 1 · 3 1 lb-l-60 0. 0 0 12 6 1 la-1-61 0. 2 4 7 lb-1-61 0.247 6 2 lb-1-62 3.5 0 6 3 ~ la-1-63 1 · 0 5 lb-1-63 0. 0 0 0 3 9 6 4 la-1-64 1. 9 0 lb-1-64 0 0 0 3 7 6 5 la · 1-65 • 0 '2 9 1 lb-1-65 0, 0 0 3 5 105- 200403216 Table 4 9 Example No./ Compound No. I c50 (uU) Compound No. I Cs〇 (uU) 6 7 la-1-67 lb-l.Gi 0,0 0 6 1 6 8 la-1-68 0.231 8 0 la * 1-80 1.9 1 8 3 la-1-83 1 · 7 7 8 5 la-1-85 1. 2 lb-1 -85 0.013 8 6 la-1-86 0.3 5 lb-1-86 0. 0 0 5 3 8 7 lb-1-87 0.940 9 3 la-2-2 0 · 2 3 7 9 4 la-2-3 0. 0 10 9 9 5 la-2.4 0. 0 7 5 9 9 6 la-2-5 0.123 9 7 la-2-6 0.088 9 8 la-2-7 0. 0 6 9 9 10 0 la-2 -9 0. 0 5 7 7 10 1 la-2-10 0.023 10 2 la-2-11 0. 0 4 7 5 10 3 la-2 · 12 0. 0 9 8 1 10 4 la-2-13 3.2 8 10 5 la-2-14 2,9 8 10 6 la-2-15 0. 13 3 10 7 la-2-16 0.325 10 9 la-2-18. 1.19 110 la-2-19 0.203 111 1e * 2 * 20 3. 4 1 112 la-2-21 3.7 4 114 la-2-23 0.929

• 106- 200403216 Table 5 〇 Example No. Compound No. I Cso (/ zM) 115 la-2-24 0. 16 1 117 13.-2 * 26 1.19 118 la-2-27 0.088 119 la-2- 28 1.11 12 0 La-2-29 1.5 3 12 1 la-2-30 0. 0 7 3 6 12 2 la-2-31 0.224 12 3 la-2-32 0. 0 2 3 4 12 4 la-2 -33, 0 · 0 2 18 12 5 la-2-34 0. 0 144 12 6 σ. 1 5 6 12 7 1 18.-2 * 36 0.0 2 4 3 12 8 la-2-37 0. 0 9 2 2 12 9 la-2-38 0.222 16 0 la-3-2 0.040 16 1 1sl * 3 * 3 0. 0 10 8 16 2 la-3-4 0. 8 7 3 16 3 la-3-5 0 0 12 6 16 4 la-3-6 0 · 0965 16 5 la-3-7 0.230 16 6 la-3-8 1. 28 16 7 la-3-9 • 0.014 16 8 la-3-10 0. 0 0 8 3 16 9 la-3-11 0.244 1 7 0 la-3-12 2 · 0 3 17 1 la-3-13 0. 0 3 9 5 ~ ·: 4 i;; ζ- 107- 200403216 Table 5 1 Example No. Compound No. I Cso (uM) 17 7 la-4-2 0, G 8 4 17 8. La-4-3 0. 0 2 5 2 17 9 la-4-4 2.3 6 18 0 la-4-5 0.04 5 18 1 la-4-6 0. 0 5 3 9 18 2 la-4-7 0. 0 0 5 9 18 3 la-4-8 0. 0 0 2 7 18 4 la-4-9 0. 0 0 3 2 5 18 5 la-4-10 0, 0 4 2 2 18 6 la-4-11 0. 0 9 8 2 18 7 la-4-12 0. 17 7 18 8 la-4-13 0. 8 4 3 18 9 la-4-14 0. 0 3 7 5 19 0 la-4-15 0. 0 5 9 7 19 1 la-4-16 0. 0 0 9 5 19 2 la-4-17 0.324 19 3 la -4-18 0.722 19 5 la-4-20 1. X 19 6 la-4-21 0. 0 5 7 3 19 7 la-4-22 0. 0161 19 8 la-4-23 0.493 19 9 la- 4-24 2.0 6 2 0 0 la-4-25 0.173 2 0 1 la-4-26 0,252 2 0 2 la-4-27 0. 0 114 2 0 3 la-4-28 0.173

-108- 200403216 Table 5 2 Example No. Compound N ο. Ic50 (βΜ) Compound No. I C50 (μΜ) 2 D 4 la-4-29 3.9 5 2 0 7 la-4-30 4. 44 2 10 lsi-5-2 0. 0 2 4 2 11 la-5-3 0. 2 10 lb-211 0. 0 0 5 6 5 2 12 la-5-4 0 · 3 9 3 2 13 la-5 -5 0, 12 8 2 14 ls.-5-6 0. 8 3 2 2 15 la-5-7 0. 1 1 0 2 16 0. 1 0 7 2 18 la-5-10 0 · 7 4 4 2 19 la-5-11 0. 5 7 4-2 2 0 la-5-12 0. 0 16 7 s. 2 2 1 la-5-13 0. 3 1.6 2 2 2 la-5-14 0. 0 7 8 2 2 3 la-5 · 15 0. 3 4 9 2 2 4 la · 1-16 0 · 0Ί 0 1 2 2 5 la-5-17 0. 0 12 2 2 2 6 la-5-18 0. 16 6 2 2 7 la-5-19 0 · 0 19 8 2 2 8 la-5-20 0. 10 6 2 2 9 la-5-21 0 · 2 15 2 3 0 la-5-22 0 . 2 8 1 2 3 1 'la-5-23 0, 19 7 2 3 2 la-5-24 0 · 1 44 2 3 3 la-5-25 0. 0 8 6 4 2 3 4 la-5- 26 0. 15 3 200403216 Table 5 3 Example No. Compound No. I C50 (μM): Compound No. I C50 (/ iM) 2 3 5 la-5-27 0.265-2 3 6 la-5-28 0.304 2 3 7 la-5-29 1.3 2 2 3 8 la-5-30 2.8 5 2 3 9 la-5-31 0. 2 4 3 2 4 0 la-5-32 0. 0 0 4 1 2 4 1 la-5-33 0 · 0131 2 4 2 la-5-34 0. 0 2 3 9 2 4 3 la-5-35 0. 0 5 2 9 2 4 4 la-5-36 0. 0 16 5 2 4 5 la-5-37 0. 0 0 5 9 2 4 6 la-5-38 0. 0 10 8 2 4 7 la-5-39 0. 0 0 3 5 2 6 7 la -2-66 1. 5 lb-2-66 0.011

Table 54 Example No, Compound No. ICS0 UM) 2 5 2 1-252 0. 2 4 2 5 3 1-253 0, 0 0 0 0 3 9 2 5 4 1-254 0e 0 0 6 3 2 5 5 1-255 0.529 2 5 6 1-256 0.601 2 5 7 1-257 0.776 '258 1-258 0.908 2 5 9 1-259 0.130 2 6 0 1-260 0.159 2 6 1 1-260 0-182 γ · <Ί ^ ν ;. -110- 200403216 The compound of the present invention exhibits a strong Iv-type collagenase inhibitory activity. INDUSTRIAL APPLICABILITY The compounds of the present invention have potent metalloproteinase inhibitory activity, especially MMP inhibitory activity, so they can be used to prevent deformable arthritis, joint rheumatism, corneal ulcer, periodontal disease, tumor metastasis or infiltration, and viral infection (Such as HIV infection), occlusive arteriosclerosis, atherosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, scleritis, multiple sclerosis , Open-angle green cataract, retinopathy, proliferative retinopathy, angiogenic green cataract, pterygium, keratitis, vesicular epidermal peeling, dry addiction, diabetes, nephritis, neurological disease, gingivitis, tumor proliferation, Tumor angiogenesis, eye tumor, angiofibroma, hemangiomas, fever, bleeding, coagulation, cachexia, loss of appetite, acute infection, shock, autoimmune disease, malaria, clonal disease, meningitis, and gastrointestinal ulcer. Example Example 1 8

CONHOH 200403216 First process compound (XV-1 8) 30 Omg of dichloromethane 4.5 ml suspension was added with bis (trimethylsilyl) acetamidine 0.67 ml and stirred for 20 minutes, then triethylamine 0.3 8ml stirring for 5 minutes, water cooling and adding biphenylbenzenesulfonyl chloride 3 7 5 mg of dichloromethane 1 · 5 m 1 solution, 30 minutes at the same temperature ... room temperature 4 · 5 hours after stirring with 2N-hydrochloric acid It was extracted with dichloromethane, washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain 339 mg of the compound (Ia-18) with a melting point of 208-211 ° C. The yield was 57.3%. Elemental analysis; C23HisN2F〇4S · 0.2H2O Φ Calculate 値 C; 62.49 Η; 4.42 Ν; 6.34 F; 4.30 S; 7.25 実 験 値 C; 62.38 Η; 4.62 N; 6,35 F; 4.13 S ; 7.31 m NMR (&lt; 5 ppm CDaOD): 3.10-3.30 (m, 2H), 4.19 (t, J = 5.26 Hz, 1H), 6.82 (m, 1H), 7.08- 7.22 (m, 3H), 7.40 -7.60 (m, 7H), 7.70-7.78 (m, 2H). In a 2.5ml solution of 250 mg tetrahydrofuran of the second process compound (Ia-18), add 0.074ml of grasshopper chlorine and 30% DMF / in a cold nitrogen atmosphere. One drop of a tetrahydrofuran solution was stirred at room temperature for 30 minutes to prepare ammonium chloride. To 2 ml of 198 ml of hydroxylamine hydrochloride in water and 2 ml of tetrahydrofuran solution were added sodium bicarbonate 28 7 mg under ice-cooling stirring. After stirring for 5 minutes, the above tetrachlorofuran tetrahydrofuran solution was added in 5 minutes. After stirring at the same temperature for 30 minutes, 15 ml of water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (dichloromethane / methanol = 9/1), followed by benzene. / Methanol lyophilized to obtain 164 mg of compound (Ib-18). The yield was 63.3%.

-112- 200403216 Elemental analysis; C23H2〇N3F〇4S · 0.5H2〇 Calculated 値 C; 59,73 Η; 4.58 Ν, · 09 · 09 F; 4.11 S; 6.93 実 験 値 C; 60.02 Η, · 4 · 46 Ν; 8.92 F; 4.12 S; 6.75 m NMR. ((5 ppm deDMSO): 2.72 (dd, J = 8.5, 14.5 Hz, 1H), 2.90 (dd, J = 8.5, 14.5 Hz, 1H), 3.82 (dd, J = 6.4, 8.2 Hz, 1H), 6-75 (m, 1H), 7.02-7.18 (m, 3H), 7.40-7.60 (m, 7H), 7.62-7.72 (m, 2H), 9,60 (br, 2H), 10.82 (brs, 1H). Example 3 9

Boc-HN ^ COOBn XV-39-1 I—S02NH ^^ C00Bn XV-39-2

2nd process 5.0g of the compound (XV-39-1) in 1st process was dissolved in 10 ml of dichloromethane, 1.5 2 ml of methoxybenzene and 10 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. Ethyl acetate, basified with sodium bicarbonate water. The ethyl acetate layer was washed with saturated brine, dried over potassium carbonate, and concentrated under reduced pressure. The obtained amine was dissolved in 40 ml of dichloromethane, 1.82 ml of N-methylmorpholine and 4.0 3 g of p-iodobenzenesulfonyl chloride were added under ice-cooling, and the mixture was stirred at room temperature for 3 hours, followed by 1N hydrochloric acid, 5% by weight. Washed with sodium carbonate water and water, concentrated under reduced pressure, and recrystallized from acetone / n-hexane by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to obtain a compound having a melting point of 118-119 ° C (XV -3 9-2) 5.5 3 g. Yield: 78%. 200403216

Elemental analysis; C24H21N2IO4S calculation 値 C; 51.44 Η; 3.78 Ν; 5.000 Ι; 22 · 64 S; 5.72 実 験 値 C; 51.54 Η; 3.85 Ν; 4,95 Ι; 22 · 34 S; 5.73 (α) Ό +17.3 (c = 0.5, DMSO 22 × :) IR (ν cm 1 KBr): 3413, 3284, 1743, 1336, 1162 ΉNMR (δ ppm CDCls): 3-10-3.34 (m, 2H), 3.53 (s, 3H), 4.25 (m, 1H), 5.17 (m, 1H), 6.96-7.47 (m, 7H), 7.60-7.71 (m, 2H), 8.05 (br s, 1H). Compound 2 (XV- 3 9-2) 5 00 mg was dissolved in 10 ml of dry THF, 370 mg of powdered potassium carbonate, 203 mg of 3-methoxyphenylboronic acid, and 52 mg of triphenylphosphine palladium were added. The mixture was heated at 75 ° C under Ar atmosphere for 48 hours under reflux, and ethyl acetate Diluted, washed with 1N-hydrochloric acid, 5% sodium bicarbonate water and water, dried over sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to obtain the compound (XV -3 9-2) 327 mg. Yield 68%. Elemental analysis; C3lH28N205S.a2H2. Calculated 値 C; 68.42 Η; 5.26 Ν; 5.15 S; 5.89 実 験 値 C; 68.37H; 5.23N; 5.04S; 5.74 [α] Ό +4.1 (c = 1.0, CHCI3 26 ^) IR (v cm! CHCI3): 3405, 1735, 1337, 1159 Ή NME (δ ppm CDCla): 3.28 (d, J ^ 5.8 Hz, 2H) „3.87 (s, 3H), 4 , 37 (dt, J = 9 * 4, 5.8 Hz, 1H), 4.76 and 4.84 (AB q, J-12.0 Hz, 2H), 5.20 (d, J -9.4 Hz, 1H), 6.85-7.80 (m, 18H), 7.96 (br s, 1H). 270 mg of compound 3 (XV-3 9-3) was dissolved in 4 ml of dioxane and 4 ml of methanol, with a strength of 10% P d C 5 3 mg, and stirred in a hydrogen atmosphere. After 3 hours, the catalyst was filtered off and concentrated under reduced pressure to obtain 1 98 mg of foamy compound (Ia-3 9). Yield 88%

-114- 200403216 Elemental analysis: C24H22N2〇5S * 0.8H2〇Calculate 値 c; 62.00 Η; 5.12 N; 6.03 S; 6.90 実 験 値 C; 62.03 Η; 5.06 Ν; 6.03 S; 6.82 [οφ +26.0 (c = 1.0, DMSO 23 ° C) IR (v cm · 1 KBr): 3412, 1724, 1326, 1159 m NMR (&lt; 5 ppm dsDMSO): 2.89 (dd, J ^ 7.8, 14.2 Hz, 1H ), 3.09 (dd, J = 5.8, 14.2 Ηζ, ΙΗ), 3.90 (m, 1H), 3.85 (s, 3H), 6.85 ^ 7.11 (m, 4H), 7 J7-7.48 (m, 5H), 7.56 -7.72 (m, 2H), 8.23 (br s, 1H), 10.80 (s, 1H). Example 5 7

The first process compound (χ V-5 7) 4 0 8 mg was suspended in dioxane 20 m 1 and water 10 m 1, and the mixture was stirred under ice-cooling, followed by sodium carbonate 4 2 4 mg and dimethylaminonaphthalenesulfonate. 540mg of Chlorine (manufactured by Aldrich), slowly raised to room temperature and stirred for 15 hours, poured into water, adjusted to pH = 4 with 10% citric acid, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under reduced pressure , Column chromatography on silica gel (chloroform / methanol = 10/1), 500 mg of compound (la-57) with a melting point of 1 8 7-1 90 ° C was obtained. The yield is 57%. Elemental analysis; C23H23N3〇4S · 1.7H20 c 'Calculate 値 0; 59 · 01 Η; 5.68 Ν; 8.98 S; 6.85 実 験 値 C; 59.07 Η; 5.26 Ν; 8.72 S; 6.38 [a] D- 69 · 2 2.1 (c = 0.516% DMSO 22 × :) IR (v cm · 1 KBr): 3413br, 1588, 1457, 1411, 1357, 1308, 1141 Ή NMR (δ ppm d6DMSO): 2.81 (s, 6H) , 3,03 (dd, J = 5.4, 18.0 Hz, 1H), 3.10 (dd, J = 5.4, 18.0 Hz, lH), 3.57 (m, 1H), 6-88 (m, 1H), 6.97 ^ 7.02 (m, 2H), 7.19-7.27 (m, 3H), 7.42-7.55 (πι, 3H), 8.05 (d, J = 6.9 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.39 ( d, J = 8.4 Hz, 1H), 10.66 (s, 1H). -115- 200403216 Example 74 1st process I H2N Eight COOH XV-74

la-74 204 mg of compound (XV-74) in the first process was dissolved in 8 ml of dioxane and 4 m of water. Under ice-cold stirring, 212 mg of sodium carbonate and 5-chloro-3-methylphenylhydrazone [b] thiophene-2- 281 mg of sulfonium chloride (manufactured by Maybridge), slowly raised to room temperature and stirred for 3.5 hours, then poured into water, adjusted to 10% ~ 4 with 10% citric acid, extracted with ethyl acetate, washed with water, and sulfuric acid Sodium was dried, concentrated under reduced pressure, and then subjected to silica gel column chromatography (chloroform / methanol = 10/1) to obtain 260 mg of a compound (Ia-74) having a melting point> 2 50 × :. Yield: 58%. [a] D -40 · 8 ± 1,6 (c = 0.510% DMSO 22C) IR (v cm ·! KBr): 3421br, 1580, 1421, 1333, 1153 Ή NMR (6 ppm deDMSO): 2.41 (s, 3H), 3.01 (dd, J = 6.0, 14,4 Hz, 1H), 3.12 (dd, J = 4.5, 14.4 Hz, 1H), 3.67 (t, J = 5.4 Hz, 1H), 6.79 (m, 1H ), 6,89 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.51 (dd , J = 1.8, 8.7 Hz, 1H), 7,86 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 10,50 (s, 1H). -116- 200403216 Example 8 6

1st process XV-86-1 2nd process

_ _ P (H3C) 2NH ^) ~ N = N-h ^)-S〇2NH VIII COOteu XV-86-2

(Η3〇) 2N ·-^^^ N = N — ^^-* S〇2NH ^ COOH la-86

H2N eight CONHC ^ Bu third process (H3C) 2N-^^-N = N-(^ &gt; -S02NH eight α) ΝΗ (Λ

XV-86-3 4th process XV-86-4

(H3C) 2N-h ^^ N = N-^^ &gt; -S02NH 2 CONHOH lb-86 1st process

221 mg of the compound (XV-86-1) was dissolved in 8 ml of dichloromethane, 0.5 6 ml of triethylamine and 40 5 mg of puertochlor were added, and after stirring at room temperature for 2.5 hours, water and ethyl acetate were added and stirred. The crystals collected by filtration were sequentially washed with ethyl acetate and water and dried to obtain 414 mg of compound (XV-86-2). The yield was 82%. (οφ · 101 · 5 soil 7.0 (c = 0.203% DMSO 25T :) IR (v cm-1 KBr): 3425, 3301, 1716, 1370, 1140 Ή NMR (δ ppm deDMSO): 1.11 (s, 9H ), 2.79 (dd, J = 8.4, 13.7 Hz, 1H), 2.88 (dd, J = 7.4, 13.7 Hz, 1H), 3.09 (s, 6H), 3.90 (m, 1H), 6.86 (d, J = 9.0 Hz, 2H), 7.11-7.32 (ιιι, 6H), 7.70 «7.92 (m, 5H). Compound 2 (XV-86-1) 3 8 6 mg was dissolved in 10 ml of dichloromethane, and trifluoroacetic acid 1 was added. 0 ml, and stirred at room temperature for 2 hours. After concentration under reduced pressure, it was washed with diethyl ether / 200403216 n-hexane to obtain 429 mg of the compound (Ia-8) with a melting point of 93-94 ° C. [a] D -14.3 ± 2.2 (c = 0.251% DMSO 25.5X :) IR (v cm ^ KBr): 3700-2200br, 3431, 1735, 1391, 1154 m NMR (&lt; 5 ppm deDMSO): 2.74 (dd , J = 9.1, 13.6 Hz, 1H), 2.96 (dd, J = 5.7, 13.6 Hz, 1H), 3.09 (s, 6H), 3.93 (dt, J = 5.7, 9.1 Hz, 1H), 6.86 (d, J = 9.3 Hz, 2H), 7.10 ^ 7.38 (111, 5H), 7.69 (d, J-8.7 Hz, 2H), 7,76 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 9.3 Hz, 2H), 8.39 (d, J = 9, 1 Hz, 1H). Compound 3 (XV-86-3) 260mg is dissolved in 5ml of dimethylformamide and 70.7mg of hydroxybenzitriazole 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 92.5 mg, N-methylmorpholine 0.3 ml. After stirring under ice-cooling for 1 hour, □-(tert-butyl) hydroxylamine hydrochloride was 76 · 3 mg. After stirring at room temperature for 18 hours, it was poured into water, extracted with ethyl acetate, washed with water, concentrated under reduced pressure, and subjected to silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to obtain the compound (XV-86-4 ) 1 42mg. Yield: 59%. Ή NMR (δ ppm CDCla): 1.20 (s, 9H), 2.90-3.04 (m, 2H), 3.14 (s, 6H), 3.90 (m, 1H), 4.97 (d, J = 6, 6 Hz, 1H ), 6.78 (d, J = 9.0 Hz, 2H), 6.96-7.02 (m, 2H), 7.14-7.25 (m, 3H), 7.72 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 8.33 (s, 1H). 15.4 mg of compound (XV-86-4) in the fourth process was dissolved in 0.5 mg of dichloromethane, and trifluoro was added 1 ml of acetic acid was stirred at room temperature for 7.5 hours. After heating at 60 ° C for 1 hour, it was concentrated under reduced pressure and washed with diethyl ether / n-hexane to obtain 3.9 mg of the compound (la-86). The yield was 23%. lR NMR (δ ppm deDMSO): 2.71-2.88 (m, 2H), 3.09 (s, 6H), 6.86 (d, J = 9.0 Hz, 2H), 7,83 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 8.4 Hz, 4H), 8.36 (s, 1H), 10.64 (s, 1H). -118- 200403216 Example 248 Η

BocHN COOBn XV-248-1

NC

2nd process · S02NH… COOBn XV-248-2

N = N / z = \

Third process

HN —U ^ -S02NH Eight COOBn ΧΝΛ248-3

^ SOaNH COOH la-248 Process 1 1.5 g of compound (XV-248-1) was dissolved in 6 ml of dry THF and 6 ml of dichloromethane. Under ice-cooling, 0.46 ml of N-methylmorpholine and a solution of 4-cyanobensulfonium chloride 8 4 3 mg in dichloromethane 15 m 1 were added. After stirring at room temperature for 1 hour, ethyl acetate was added, and the mixture was sequentially washed with 2N-hydrochloric acid, 5% sodium bicarbonate water and water, dried over sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (n-hexane / acetic acid). Ethyl ester = 1/1), crystallized from n-hexane to obtain 1.32 g of a compound (XV-248-2) with a melting point of 1 5 3-1 5 5 ° C. The yield was 76.7%. [a] D + 22 · 2 ± 0.6 (c = 1.0 %% DMSO 22X :) IR (y cm-1 KBr): 3392,3330,2236,1748,1347,1159 Ή NMR (δ ppm CDCls): 3.18 ( dd, J = 7.0, 14.8 Hz, 1H), 3.29 (dd, J = 5.0, 14.8 Hz, 1H), 4.31 (m, 1H), 4.69 (s, 2H), 5.33 (d, J = 9.0 Hz, 1H ), 6.85-7.70 (m, 14 H), 8.01 (s, 1H). 600 mg of compound 2 (XV-248-2) was dissolved in 10 ml of 1-methyl-2-pyrrolidone, and sodium azide was added 426 mg, 451 mg of triethylamine hydrochloride, heated and stirred at 75 ° C for 6 hours, diluted with ethyl acetate, washed with 1N-hydrochloric acid and saturated brine, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform / methanol / Water = 32/9/1) to obtain 581 mg of a white powdery compound (xv-248-3).

-119- 200403216 Yield 96%. (Q〇d -12 · 4 土 a5 (c = 1.009% DMSO 23t :) IR (V cm * 1 KBr): 3420br, 1736, 1457, 1421, 1338, 1162 Ή NMR (5 ppm d6DMSO): 2.95 (dd , J = 7.0r 14.2 Hz, 1H), 3.11 (dd, J = 8.2, 14.2 Hz, 1H), 4.10 (dt, J = 7.8S 7.8 Hz, 1H), 4.75 (s, 2H), 6.84-7.10 ( m, 5H), 7.13-7.34 (m, 5H), 7.71 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 10.88 (^ 1H). 3rd process compound (XV -2 48- 3) 4 0 0 mg is dissolved in 3 ml of dioxane and 3 ml of methanol, and 10% P d-C 2 0 3 mg. After stirring in a hydrogen atmosphere for 2 hours, the catalyst is filtered off and concentrated under reduced pressure. This gave a bubbly compound (Ia-24 8) 3 3 5 mg. 85% yield elemental analysis; CwHieNeC ^ S · 0.4H20 Calculate 値 C; 51-52 Η; 4.04 N; 20,03 S; 7.64 実 験 値 C; 51.34 Η; 3.96 N; 19.76 S; 8.02 [ a) D + 23 · 2 ± 0 · 6 (〇 = 1.004% DMSO 23 * 0) IR (v cm-1 KBr): 3405, 3099, 1698, 1430, 1327, 1163 Ή NMR ((5 ppm deDMSO ): 2.87 (dd, J = 8.2, 14.4 Hz, 1H), 3.09 (dd, J = 5.4, 14.4 Hz, 1H), 3.96 (m, 1H), 6.80-6.94 (m, 2H), 7.00-7.28 ( m, 2H), 7.30 (m, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7,95 (d, J = 8.6 Hz, 2H), 8.46 (d, J = 8.6 Hz, 21H), 10.75 (s, 1H), 12.71 (brs, 1H). Example 267 200403216

2nd process

S02NH XV-267-2 j〇 1st process I *-: ---

HgN ^ COO ^ u Χν-267 · 1

COCfeu XV-267-3 3rd process Ο

S02NH Eight COOH process 4 la-267

lb-267 2.22 g of compound (XV-267-1) in the first process was dissolved in 23 ml of dichloromethane, 2.2 ml of N-methylmorpholine and 3.04 g of p-iodobenzenesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 1 After 6 hours, wash sequentially with 1 N hydrochloric acid, 5% sodium bicarbonate water and water, concentrate under reduced pressure, and recrystallize from ethyl acetate / n-hexane to obtain a compound with a melting point of 1 16-1 17 ° C. (XV-2 6 7-2) 3 · 4 4 g. The yield was 71%.

Elemental analysis; Ci9H22NI〇4S calculation 値 Q46.83 Η; 4.55 N; 2.87 I; 26,04 S; 6.60 実 験 値 C; 46.69 Η; 4.58 N; 2,92 I; 26.02 S; 6.55 [a ] D · 12 · 7 (c = 0,503, (^ 013 221) IR (v cm · 1 KBr): 3425, 3279, 1720, 1352, 1171, 1153 Ή NME (δ ppm CDCh): 1.24 (s, 9H ), 2.99 (d, J = 6.0 Hz, 2H), 4.06 (dt, J = 6.2, 9.3 Hz, 1H), 5.10 (d, J = 9.3 Hz, 1H), 7.09-7.15 (m, 2H), 7.22 -7.28 (m, 3H), 7.45 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.7Hz, 2H). 2nd process

500 mg of compound (XV-2 67 -2) was 157 mg of acetylenebenzene dissolved in 5 ml of DMF 200403216, and 18 mg of bis (triphenylphosphine) palladium (II), 10 mg of copper iodide and triethylamine 0. 2 9 m 1 , Stir at 50 ° C for 15 hours under Ar flow, pour into cold water, acidify with 2N-hydrochloric acid, extract with ethyl acetate, wash with 5% sodium bicarbonate water and water, and dry with anhydrous sodium sulfate Dried, concentrated under reduced pressure, and recrystallized from ethyl acetate / n-hexane on silica gel column chromatography (toluene / ethyl acetate = 1/5) to obtain a compound having a melting point of 1 2 3-1 2 4 ° C (XV · 2 6 7-3) 3 50 mg. The yield was 74%.

Elemental analysis; C27H27NO4S

Calculate 値 C; 70.26 Η; 5.90 Ν, 3.03 S; 6.95 実 験 値 C; 70.31 Η; 5.76 Ν; 3.04 S; 6.96 IE (v cm · 1 KBr): 3440br, 3309, 2218, 1705, 1429, 1344, 1296, 1159 Ή NMR ((5 ppm CDCb): 1.23 (s, 9H), 3.03 (d, J = 5.8 Hz, 2H), 4.10 (dt, J = 6.2, 9.2 Hz, 1H), 5.13 (d, J = 9.2Hz, 1H), 7.10-7.17 (m, 2H), 7.21 ^ 7, 28 (ιη, 3H), 7.34-7.40 (m, 3H), 7.50-7.60 (m, 1H), 7.7〇.7.77 (m, 2H). 276 mg of compound (XV-267-3) in the third process was dissolved in 2.5 ml of dichloromethane, 5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 24 hours and then concentrated under reduced pressure. And washed with ether / n-hexane to obtain a compound (Ia-267) 22 1 mg at a melting point of 1 76-178 at 8 ° C. Yield 9 1%. [A] D -9.9 ± 1.0 (c = 0.503%) DMSO 24.5eC) IR (v cm · 1 KBr): 3700-2400br, 3427, 3289, 2213, 1721, 1694, 1347, 1163 Ή NMR (δ ppm d6DMSO): 2.73 (dd, J = 9.3, 13.5 Hz, 1H ), 2.96 (dd, J = 5.4, 13.5 Hz, 1H), 3.92 (dt, J = 5.4, 9.3 Hz, 1H), 7.11 «7.23 (m, 5H), 7.42-7.50 (m, 3H), 7.52- 7.64 (m, 6H), 8.42 (d, J = 9.3 H z 5 1H) ° Compound 4 (Ia- 2 6 7) 20 3 mg was dissolved in 3 ml of DMF, 85.5 mg of 1-hydroxybenzopyrazole was added, 1-ethyl-3 -(3-Dimethylaminopropyl) carbodiimide salt

-122- 200403216 acid salt U5mg, N-methylmorpholine 0.3m Bu under stirring under ice-cooling for 1 hour. Add 5 2 · 3 mg of hydroxylamine hydrochloride, stir at the same temperature for 2 hours, pour into water, extract with ethyl acetate, wash with water and concentrate under reduced pressure. Column chromatography on silica gel (n-hexane / ethyl acetate = 1) / 2), to obtain 76.8 mg of compound (Ib-267) with a melting point of 156-1 58t. The yield is 37%.

Elemental analysis; C23H2〇N2〇4S · 0.1HsO calculation 値 C; 65,42 42; 4.82 Ν; 6.63 S; 7.59 実 験 値 C; 65.31H; 5.00N; 6.40S; 7.62 [a] D -1.6 ± 0.8 (c = 0.500, DMSO 25.5t :) IR (v cm * 1 KBr): 3700-2400, 3267, 2217, 1671,1321, 1161 Ή NMR (6 ppm deDMSO): 2.62 (dd, J = 8,6, 13.5 Hz, 1H), 2.80 (dd, J = 6.0, 13.5 Hz, 1H), 3.82 (dt, J = 6-0, 8.6 Hz, 1H), 7.03-7.22 (m, 5H) , 7.42-7.50 (m, 3H), 7.52.7.63 (m, 3H), 8.38 (d, J = 8.6 Hz, 1H), 8.87 (d, J = 1.5 Hz, 1H), 10.64 (d, J = 1.5 Hz, 1H).

Claims (1)

200403216 Patent application scope: 1 · A compound of formula I, its optically active substance or their pharmaceutically acceptable salt COY R5-R4-R3-S〇2-N R2 where R1 can be selected from halogen, C3 ~ C8 cycloalkyl, hydroxyl, carboxyl, and benzene (^ ~ c3 alkoxy substituted Ci ~ c6 alkyl, phenyl, may be substituted by a substituent selected from phenyl, nitro, halogen, hydroxyl, and carboxyl Substituted phenyl Ci ~ C6 alkyl or naphthyl &lt; ^ ~ (: 6 alkyl, or may be selected from Ci ~ C6 alkyl, Ci ~ C6 alkoxy, halogen, Ci ~ c6 alkylsulfonyl, Ci ~ C6 alkoxycarbonyl, Ci ~ c6 alkylcarbonyl, and indole substituted by indole Ci ~ C6 alkyl, thiazole Ci ~ c6 alkyl, benzothiazole C6 alkyl, pyridine Ci ~ C6 alkyl, or Benzimidazole Ci ~ c6; R2 is hydrogen, C6 alkyl which may be substituted by amine, or phenyl (^ ~ C6 alkyl); R3 is phenyl which may be substituted by nitro or C6 alkoxy, Or thiophene diyl; R4 is a single bond, R5 is a C3 ~ C8 cycloalkyl, can be selected from halogen, halogen Ci ~ c6 alkyl, ... ~ c6 alkyl, c3 ~ c8 ring courtyard, C2 ~ C6 dilute , C2 ~ Quick base, Jing base, Alkyl, C! • 124- 200403216 ~ C6 alkoxy, (^ ~ C6 alkylthio, carboxyl, Ci ~ c6 alkoxycarboxyl, carbamoyl, nitro, cyano, can pass C! ~ C6 alkyl A substituted amine group, a phenyl group, a phenoxy group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a phenyl group, a substituted group, Or naphthyl, thienyl, benzoxazolyl, benzoxazolyl, diphenylsulfanylfuranyl, pyridyl, tetrazolyl, substituted with a substituent selected from halogen and (^ ~ (: 6 alkyl), Phenylthiophene, pyrazolyl or isoxazolyl, or morphinyl; Y is NHOH or 0H; but when Y is NΗ0Η, R2 is hydrogen, and when R3 is nitro or (^ ~ 〇6 院) Oxygen-substituted phenyl, r5 can be substituted by 1 ~ (: 6 phenyl, Cl ~ c6 oxy, Ci ~ C6 alkylthio, halogen, halogen (^ ~ (^ 6 phenyl or phenyl substituted Phenyl, or phenyl substituted by phenyl, phenylhydrazone, phenylbenzoyl, diphenylfuranyl, pyridyl, tetrazolyl, phenylphenanyl, pyrazolyl, or isopropyl Oxazolyl. 2 · If the compound in the scope of patent application No. 1, Or the like of the optically active substance and pharmaceutically acceptable salt thereof, the system shown in formula IV 200403216 In the formula, R 11 is a single bond, and R 7 is an alkyl group selected from halogen, halogen Cl ~ C6, and halogen. ~ C6 alkyl, c3 ~ C8 cycloalkyl, C2 ~ C6 alkenyl, C2 ~ c6 alkynyl, hydroxyl, mercapto, Ci ~ C6 alkoxy, Ci ~ C6 alkylthio, carboxyl, Cl ~ c6 alkoxycarboxy Carbamoyl group, nitro group, cyano group, fee group which can be substituted by Ci ~ C6 alkyl group, this group, phenoxy group, (^ ~ (^ 院 矿 基基, (^ ~ () 6 Phenyl, or naphthyl, substituted with a substituent of Cl ~ C6 alkylsulfonyl, or thienyl, benzoxazolyl, which may be substituted with a substituent selected from halogen and C ^ alkyl , Benzoxazolidyl, diphenylsulfanyl furanyl, pyridyl, tetrazolyl, benzoxanthienyl, pyryl, or isoxazolyl; X is a sulfur atom; R1, R2, and Y are the same as those in the scope of the patent application 3. The compound of item 1 of the scope of patent application, its optically active substance or their pharmaceutically acceptable salt, which is represented by the following formula I "R1 &quot; r5 &quot; 〇3 &quot; _s0 1 Human C0Y Γ Br s formula Where R1 ”is 4-thiazolylmethyl, (indol-3-yl) methyl, (5-methoxyindol-3-yl) methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4 -Biphenylmethyl, 2,2, 2-trifluoroethyl, 2-phenethyl Benzyl, Isopropyl, 4-Nitrobenzyl, Enfluorobenzyl, Cyclohexylmethyl, (Methylindole · 3-yl) methyl, (5-methylindole-3 -yl) methyl , (5-fluoroindole-3 -yl) methyl, (pyridin-4-yl) methyl, (benzimidazol-2-yl) -126- 200403216 methyl '(benzyl) (anhydrobenzyl) methyl Methyl, phenyl, carboxymethyl, 2-carboxyethyl, light methyl, methoxymethyl, 4-residue; methyl, (benzimidazol-2-yl) methyl, (1-methylsulfonyl) Indole_3_yl) methyl, or (buethoxycarbonylindol-3-yl) methyl, R2 "is H; R3" is 丨, phenylene; R4 "is a single bond; R5 ,, It is 3-methoxyphenyl, 4-methoxyphenyl, i-tolyl '4-tert-butylphenyl, 4-trifluorotolyl, 4 • fluorophenyl, 4 • methylthiobenzyl, 4-biphenyl Phenyl, 4-thienyl, benzoxazol-2-yl, benzoxazol-2-yl or tetrazol-2-yl; γ is NHOH or 0H. 4 · Compounds as described in item 1 of the scope of patent application , Its optically active substance or their pharmaceutically acceptable salt, which is shown by the following formula VIII VIII In the formula, R1 and R2 are the same as those defined in item 1 of the scope of patent application, and R7 and RU are the same as those defined in item 2 of the scope of patent application. 5. If the compound in the scope of patent application item 1, its optically active substance or their pharmaceutically acceptable salt, is represented by the following formula XIII In XIII, R1 is the same as defined in item 1 of the scope of patent application 'R7 and R11 are the same as defined in item 2 of the scope of patent application. 6. The compound as claimed in any one of claims 1 to 5, its optically active substance or their pharmaceutically acceptable salt, wherein R1 and R1 '' are isoryl, benzyl or (indole-3- Methyl). -127- 200403216 7. If the compound according to any one of claims 1 to 5, its optically active substance or their pharmaceutically acceptable salt, wherein R5 and R7 are alkoxy, alkylthio or may have 1 Or a phenyl group having two or more substituents. 8. If the compound of any one of claims 1 to 5 of the patent application scope, its optically active substance or their pharmaceutically acceptable salt, wherein the configuration of the asymmetric carbon bonded by R1 and R1 '' is R configuration . 9. A pharmaceutical composition for a metalloproteinase inhibitor, which contains a compound according to any one of claims 1 to 5 of the patent application scope. 10. A pharmaceutical composition for a type IV collagenase inhibitor, containing a compound such as any one of claims 1 to 5 of the patent application scope. -128- 200403216 (1) Designated representative map: (1) The designated representative map in this case is: (). (II) A brief description of the element representative symbols in this representative figure: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention ... r5-r4-r3-s〇2-n coy I R2